6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them

ABSTRACT

The present invention relates to compounds defined by formula (I), wherein the groups X, Y, W and R 1  to R 4  are defined as in claim  1 , possessing valuable pharmacological activity. Particularly the compounds are agonists of the 5-HT2C receptor, and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this receptor, such as metabolic and CNS-related disorders.

FIELD OF THE INVENTION

The present invention relates to novel 6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]indene derivatives that are modulators of the 5-HT2C receptor, to processes for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful for treatment of 5-HT2C receptor-associated diseases, conditions or disorders, such as, obesity and related CNS-related disorders.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine which plays a prominent role in a variety of physiological functions in both the central nervous system (CNS) and the periphery of the body. These pleiotropic effects are mediated by at least 14 different receptors which are grouped into seven families (5-HT₁₋₇) according to their primary structure and their intracellular signal transduction coupling systems (Hoyer, D., et al., Pharmacol Biochem Behav, 2002. 71(4): p. 533-54). With the exception of the 5-HT₃ receptor, which is an ion channel, all serotonin receptors are G-protein coupled receptors (GPCRs).

The 5-HT₂ receptor family consists of 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C) receptors. A number of studies suggest that the 5-HT_(2C) receptor system is specifically involved in diseases or conditions such as the metabolic syndrome including obesity, type II diabetes, and dyslipidemia, as well as CNS-related disorders including depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as, but not limited to, type II diabetes, hypertension, stroke, certain forms of cancers and gallbladder disease. Obesity has become a major healthcare issue in the Western World and increasingly in some third world countries. The increase in the number of obese people is due largely to the increasing preference for high fat content foods but also, and this can be a more important factor, the decrease in activity in most people's lives. In the last 10 years there has been a 30% increase in the incidence of obesity in the USA and that about 30% of the population of the USA is now considered obese. In spite of the growing awareness of the health concerns linked to obesity the percentage of individuals that are overweight or obese continue to increase. In fact, the percentage of children and adolescents who are defined as overweight has more than doubled since the early 1970s and about 13 percent of children and adolescents are now seriously overweight. The most significant concern, from a public health perspective, is that children who are overweight grow up to be overweight or obese adults, and accordingly are at greater risk for major health problems. Therefore, it appears that the number of individuals that are overweight or obese will continue to increase. Whether someone is classified as overweight or obese is generally determined on the basis of his or her body mass index (BMI) which is more highly correlated with body fat than any other indicator of height and weight. A person is considered overweight when they have a BMI in the range of 25-30 kg/m², whereas a person with a BMI over 30 kg/m² is classified as obese. Obesity is further divided into three classes, Class I (BMI of about 30 to about 34.9 kg/m²), Class II (BMI of about 35 to 39.9 kg/m²) and Class III (about 40 kg/m² or greater). There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.

It has been recognized that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJB Publications Ltd, 1996). As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (hypertension, coronary insufficiency, coronary heart disease, angina pectoris, congestive heart failure, atheromatous disease, cardiac insufficiency), high blood cholesterol, dyslipidemia, type II (non-insulin dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, stroke, gall bladder disease (particularly gallstones and cancer), cholescystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, some types of cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation), diseases of reproduction (such as sexual dysfunction, both male and female, including male erectile dysfunction), bladder control problems (such as stress incontinence), uric acid nephrolithiasis, psychological disorders (such as depression, eating disorders, distorted body image, and low self esteem). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

As the 5HT2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5HT2C receptor agonist can be an effective and safe pharmaceutical agent. Also, 5HT2C knockout mice are overweight with cognitive impairment and susceptibility to seizure thus establishing the clear use for a 5HT2C receptor agonist in 5HT2C receptor associated diseases or disorders. The 5HT2C receptor plays a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, 5HT2C receptor agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction. In addition, 5HT2C receptor agonists are useful for the treatment of psychiatric symptoms and behaviors in individuals with eating disorders such as, but not limited to, anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa often demonstrate social isolation. Anorexic individuals often present symptoms of being depressed, anxious, obsession, perfectionistic traits, and rigid cognitive styles as well as sexual disinterest. Other eating disorders include, anorexia nervosa, bulimia nervosa, binge eating disorder (compulsive eating) and ED-NOS (i.e., eating disorders not otherwise specified-an official diagnosis). An individual diagnosed with ED-NOS possess atypical eating disorders including situations in which the individual meets all but a few of the criteria for a particular diagnosis. What the individual is doing with regard to food and weight is neither normal nor healthy.

The first line of treatment for individuals that are overweight or obese is to offer diet and life style advice, such as, reducing the fat content of their diet and increasing their physical activity. However many patients find these difficult to maintain and need additional help from drug therapy to sustain results from these efforts.

Compounds marketed as anti-obesity agents include Orlistat and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhea. Sibutramine (a mixed 5-HT/noradrenalin reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine and dexfenfluramine have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.

The compounds of formula (I) are useful in the treatment and/or prevention of disorders involving elevated plasma blood glucose, particularly diabetes mellitus (including Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes). The diabetes maybe diabetes secondary to pancreatic disease; or diabetes related to steroid use. The compounds of formula (I) are also useful in the treatment and/or prevention of the sequelae of hyperglycemia; in the treatment and/or prevention of diabetic complications; and in the treatment of insulin dependence. The invention is of particular use in the treatment or prevention of diabetes mellitus (including Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes), and particularly in the treatment or prevention of Type II diabetes.

Diabetes has also been implicated in the development of severe sequelae such as kidney disease, eye diseases and nervous-system problems. Kidney disease, also called nephropathy, occurs when the kidney's “filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina and increases the risk of cataracts and glaucoma Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the leading causes of death.

OBJECT OF THE INVENTION

It is an object of this invention to provide selective, directly acting 5-HT2 receptor ligands, hereinafter described as compounds of formula (I), for use in prevention and/or treatment of metabolic and CNS-related disorders, particularly diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents and diseases/disorders mentioned above.

SUMMARY OF THE INVENTION

In one aspect the invention provides a compound of formula I:

as defined hereinafter, the isoforms, tautomers, stereoisomers, solvates, hydrates, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, or the combinations thereof.

The present invention further provides a composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The present invention further provides a method of modulating a 5HT2C receptor comprising contacting the receptor with a compound of formula (I).

The present invention further provides a method of treating disorders of the central nervous system, damage to the central nervous system, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, sleep apnea or HDL-related condition comprising administering to a patient in need of the treating a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of decreasing food intake of a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of inducing satiety in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of controlling weight gain of a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of treating obesity comprising administering to a patient in need of such treating a therapeutically effective amount of a compound of formula (I).

The present invention further provides a compound of formula (I), as described herein, for use in a method of treatment of the human or animal body by therapy.

The present invention further provides compounds of formula (I) for treatment or prevention of diseases or conditions which can be influenced by modulating the 5-HT2C receptor, such as metabolic and CNS-related disorders, particularly Type II diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

The present invention further provides the use of a compound of formula (I) for preparing a pharmaceutical composition which is suitable for the treatment or prevention or diseases or conditions which can be influenced by modulating 5-HT2C receptor activity, such as metabolic and CNS-related disorders, particularly diabetes, obesity, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

In some embodiments, disorders of the central nervous system include, for example, depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, agressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension. In some embodiments, sexual dysfunction is male erectile dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides in its broadest/first embodiment E-0 a compound of formula (I):

wherein:

-   X denotes a divalent 4- to 10-membered monocylic, 7- to 12-membered     spirocyclic or 6- to 12-membered bicyclic saturated, partially or     fully unsaturated group selected from a carbocycle, a     monoaza-heterocycle and a diaza-heterocycle, which is linked to the     adjacent groups via carbon atoms or, if present, via nitrogen atoms,     e.g. via one carbon and one nitrogen atom or via two nitrogen atoms, -    wherein 1 or 2 —CH₂— groups optionally are replaced independently     of each other by O, S, carbonyl, or sulfonyl, with the proviso that     two heteroatoms are not directly linked together, and/or -    1 —CH₂— group optionally is replaced by the divalent group     >C═C(R^(x))₂, wherein R^(x) independently denotes H or C₁₋₃-alkyl,     and/or -    wherein in an unsaturated group 1 double bond optionally is     condensed with an aryl or a 5- or 6-membered hetaryl group, and/or -    wherein in any of the resulting groups one or two carbon atoms     optionally and independently are substituted by halogen atoms,     C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl,     cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl,     hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl,     C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl, thiohydroxy,     C₁₋₆-alkylthio, C₃₋₆-alkenylthio, C₃₋₆-alkynylthio, amino,     C₁₋₆-alkyl-amino, C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino,     di-(C₁₋₆-alkyl)-amino, di-(C₃₋₆-alkenyl)-amino,     di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl,     C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl,     amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl,     di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl,     C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)amino-C₃₋₆-alkynyl,     hydroxycarbonyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl,     C₂₋₆-alkynyl-carbonyl, formyl, C₁₋₆-alkoxy-carbonyl,     C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino, C₂₋₆-alkenyl-carbonylamino,     C₂₋₆-alkynyl-carbonylamino, C₁₋₆-alkyl-sulphonyl,     C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl,     C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl,     C₂₋₆-alkynyl-sulphinyl, C₁₋₆-alkyl-sulphonylamino,     C₂₋₆-alkenyl-sulphonylamino, C₂₋₆-alkynyl-sulphonylamino,     aminosulphonyl, C₁₋₆-alkylaminosulphonyl,     di-(C₁₋₆-alkyl)-aminosulphonyl, C₃₋₆-alkenylaminosulphonyl,     di-(C₃₋₆-alkenyl)-aminosulphonyl, C₃₋₆-alkynylaminosulphonyl, or     di-(C₃₋₆-alkynyl)-amino sulphonyl groups, while the substituents may     be identical or different, and/or -    wherein one ring member nitrogen atom optionally is substituted by     a C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclo-C₃₋₇-alkyl,     cyclo-C₃₋₇-alkenyl, hydroxy, hydroxy-C₁₋₆-alkyl,     hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl,     C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl,     C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl,     formyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl,     C₃₋₆-alkynoxy-carbonyl, C₁₋₆-alkyl-sulphonyl,     C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl,     C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl,     C₂₋₆-alkynyl-sulphinyl, aminosulphonyl, phenyl or phenyl-C₁₋₃-alkyl     group, -   Y is absent or denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4,     5 or 6 and wherein 1 or 2 —CH₂— groups optionally are replaced     independently by O, S, carbonyl, sulfonyl, or —NH—, with the proviso     that two heteroatoms are not directly linked together, or -    wherein 1 —CH₂— group is replaced by O, S, carbonyl, sulfonyl, or     —NH—, and additionally a —CH₂—CH₂— subgroup is replaced by —C(O)—O—,     —O—C(O)—, —C(O)—NH—, or —NH—C(O)—, with the proviso that two     heteroatoms are not directly linked together, and -    wherein any hydrogen atom of the —NH— groups mentioned hereinbefore     optionally and independently is replaced by a C₃₋₆-cycloalkyl or     phenyl group, or by a straight-chained or branched C₁₋₆-alkyl,     C₃₋₆-alkenyl, C₃₋₆-alkynyl, phenyl-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl,     or C₁₋₆-alkyl-sulphonyl group, and/or -    wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally     are replaced by halogen atoms, trifluoromethyl, C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, phenyl,     phenyl-C₁₋₆-alkyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl, C₁₋₆-alkoxy-carbonyl,     C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino,     C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or     C₁₋₆-alkyl-sulphonyl groups, while the substituents may be identical     or different, or 2 geminal hydrogen atoms are replaced by a     —(CH₂)_(m)— bridge, wherein m is 2, 3, 4, or 5, -   W denotes H or an optionally substituted straight-chained or     branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1     or 2 methyl groups optionally are replaced by optionally substituted     phenyl groups or -    an optionally substituted cyclo-C₃₋₉-alkyl group, wherein     independently     -   in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to         adjacent carbon atoms optionally are replaced to form a double         bond within the ring, which optionally is condensed with an         optionally substituted aryl or an optionally substituted 5- or         6-membered hetaryl group, and the resulting group is bound via a         saturated or unsaturated carbon atom, or     -   in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the         same carbon atom (relative 1,1-position) optionally are replaced         by a C₂₋₅-alkylenyl bridge or 2 hydrogen atoms attached to         carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally         are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the         resulting polycyclic groups one or two —CH₂— groups optionally         are replaced by —NH— (or N-atoms for replacement of —CH<         members), >N—(C₁₋₆-alkyl), O, S, carbonyl, or sulfonyl, and/or         two —CH₂— groups in relative 1,3-position within a         C₄₋₅-alkylenyl bridge optionally are replaced by O atoms, and/or         2 hydrogen atoms attached to adjacent carbon atoms within a         C₄₋₅-alkylenyl bridge optionally are replaced to form a double         bond, which optionally is condensed with an optionally         substituted aryl or an optionally substituted 5- or 6-membered         hetaryl group, and/or     -   in a cyclo-C₄₋₈-alkyl group one, two or three ring members         optionally are replaced independently of each other by —NH—,         >N—(C₁₋₆-alkyl) (or N-atoms for replacement of —CH< members), O,         S, carbonyl, or sulfonyl, with the proviso that two heteroatoms         are not directly linked together, and additionally but         optionally 2 or 4 hydrogen atoms attached to adjacent ring         carbon atoms are replaced to form a double bond or two         conjugated double bonds within the ring, either of the double         bonds optionally being condensed with an optionally substituted         aryl or an optionally substituted 5- or 6-membered hetaryl         group,     -   and any of the resulting groups is bound via a saturated or         unsaturated carbon atom or a nitrogen atom, -    and wherein any of the resulting open-chained or cyclic groups     independently 1 to 4 hydrogen atoms optionally are replaced by     C₁₋₆-alkyl or C₁₋₆-alkoxy groups, and/or -    any 1 to 6 hydrogen atoms attached to carbon atoms optionally are     replaced by fluorine atoms, -   or W denotes an optionally substituted aryl or hetaryl group, -    an optionally substituted cyclo-C₃₋₈-alkyl-aryl or     cyclo-C₃₋₈-alkyl-hetaryl group, wherein the     cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are     replaced independently of each other by —NH— (or N-atoms for     replacement of —CH< members), >N(C₁₋₃-alkyl), O, S, carbonyl, or     sulfonyl, with the proviso that two heteroatoms are not directly     linked together, or -   if Y is absent W additionally denotes -    a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, 5, 6 or 7,     attached in relative 1,1-position (geminal) to a carbon atom of     group X, including the options:     -   if p is 3, 4, 5, 6 or 7 it follows that 1 —CH₂— group optionally         is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C₁₋₆-alkyl),         or     -   if p is 4, 5, 6 or 7 it follows that a —CH₂—CH₂— group         optionally is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—,         —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)-C(O)—, or         —CH═CH—, wherein the double bond optionally is condensed with an         aryl or a 5- or 6-membered hetaryl group, -    a divalent —(CH₂)_(q)— group, wherein q is 3, 4, or 5, attached in     relative 1,2-position (vicinal) to carbon atoms of group X,     including the options:     -   that 1 —CH₂— group optionally is replaced by O, S, carbonyl,         sulfonyl, —NH— or —N(C₁₋₆-alkyl)-, or     -   a —CH₂—CH₂— group optionally is replaced by —C(O)—O—, —O—C(O)—,         —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)-C(O)—,         or     -   that in the resulting 5-, 6- and 7-membered carbocyclic ring 2,         4 or 6 hydrogen atoms optionally are replaced by 1, 2 or 3 bonds         to form a partially or fully unsaturated ring with isolated or         conjugated double bonds, wherein 1 —CH₂— group optionally is         replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C₁₋₆-alkyl),         and/or one —CH═ unit is replaced by —N═, -    a divalent —(CH₂)_(r)— group, wherein r is 5, 6 or 7, attached in     relative 1,3-position to carbon atoms as binding sites of group X,     including the options:     -   that in the resulting 8-, 9- or 10-membered carbocyclic ring 2,         4, 6, 8 or 10 hydrogen atoms optionally are replaced by 1, 2, 3,         4 or 5 bonds to form a partially or fully unsaturated ring with         isolated or conjugated double bonds, and/or     -   that in the resulting 8-, 9- or 10-membered carbocyclic ring 1         hydrogen atom attached to the carbon atom in position 2 relative         to the binding sites of group X and 1 hydrogen atom attached to         a carbon atom of the —(CH₂)_(r)— group in position 6 or 7         relative to the binding sites of group X optionally are replaced         by a bond (C₀-bridge) to form a bicyclic ring system condensed         with the group X, -   R¹ denotes H, C₁₋₆-alkyl, C₃₋₆-alkenyl or C₃₋₆-alkynyl, any of those     groups being optionally substituted by 1 to 3 fluorine, chlorine or     bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or     cyclo-C₃₋₇-alkyl-group, -   R² and R³ independently denote H, halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, hydroxy or C₁₋₆-alkoxy, any of those C₁₋₆-alkyl,     C₂₋₆-alkenyl or C₃₋₆-alkynyl groups being optionally substituted by     1 to 3 fluorine, chlorine or bromine atoms, or by a cyano or     cyclo-C₃₋₇-alkyl-group, -   R⁴ and R⁵ independently denote H, halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, hydroxy or C₁₋₃-alkoxy, any of those     C₁₋₆-alkyl, C₂₋₆-alkenyl or C₃₋₆-alkynyl groups being optionally     substituted by 1 to 3 fluorine, chlorine or bromine atoms, by a     cyano, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a     phenyl or pyridyl group both optionally substituted independently by     1, 2 or 3 substituents selected from     halogen atoms, C₁₋₆-alkyl, cyclo-C₃₋₇-alkyl, cyano, hydroxy,     C₁₋₆-alkoxy, amino, C₁₋₆-alkyl-amino, or di-(C₁₋₆-alkyl)-amino     groups,     wherein, if not specified otherwise, any alkyl groups or subgroups     mentioned hereinbefore are straight-chained or branched, and     the isoforms, tautomers, stereoisomers, solvates, hydrates, and the     salts thereof, particularly the physiologically acceptable salts     thereof with inorganic or organic acids or bases, or the     combinations thereof.

TERMS AND DEFINITIONS

The term “aryl” as used herein, either alone or in combination (e.g. as a sub-moiety) with another substituent, if not otherwise specified means either an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms, for example a phenyl or a naphthyl group. Any of the aryl groups mentioned hereinbefore is optionally substituted, if not otherwise specified.

The term “hetaryl” as used herein, either alone or in combination (e.g. as a sub-moiety) with another substituent, if not otherwise specified denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic hetaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed. The ring may be linked to the molecule through a carbon atom or, if present, through a nitrogen atom. Any of the hetaryl groups mentioned hereinbefore is optionally substituted, if not otherwise specified, including substitution at carbon atoms and/or a nitrogen atom. The following are examples of five- or six-membered heterocyclic aromatic groups:

Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

The expression “substituted” or “optionally substituted” as used herein, if not otherwise specified, means that any one or more hydrogen atoms attached to the designated carbon or nitrogen atom is or optionally is replaced by a lower-molecular group, provided that the designated atom's normal valence is not exceeded and that the substitution results in a stable compound. In connection with aryl or hetaryl groups this expressions includes at least mono- di- and trisubstitution. Examples of lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds. For example the groups may comprise:

-   -   straight-chain or branched carbon chains, optionally interrupted         by heteroatoms, optionally substituted by rings, heteroatoms or         other common functional groups;     -   aromatic or non-aromatic ring systems consisting of carbon atoms         and optionally heteroatoms, which may in turn be substituted by         functional groups;     -   a number of aromatic or non-aromatic ring systems consisting of         carbon atoms and optionally heteroatoms which may be linked by         one or more carbon chains, optionally interrupted by         heteroatoms, optionally substituted by heteroatoms or other         common functional groups.

More specifically, the expression “substituted” or “optionally substituted” as used herein means substitution with a group selected from the indicated substituents or, if not otherwise specified, with one, two, three, four or more substituents attached to carbon atoms selected from the group consisting of

-   halogen atoms (fluorine, chlorine, bromine or iodine atoms),     C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₈-alkyl,     cyclo-C₃₋₇-alkenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl,     hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl,     C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl,     C₃₋₆-alkenoxy-C₃₋₆-alkenyl, C₃₋₆-alkenoxy-C₃₋₆-alkynyl,     C₃₋₆-alkynoxy-C₁₋₆-alkyl, C₃₋₆-alkynoxy-C₃₋₆-alkenyl,     C₃₋₆-alkynoxy-C₃₋₆-alkynyl, oxetanyl, tetrahydrofuranyl,     tetrahydropyranyl, pyrrolidino, piperidino, thiohydroxy,     C₁₋₆-alkylthio, C₃₋₆-alkenylthio, C₃₋₆-alkynylthio, amino,     C₁₋₆-alkyl-amino, C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino,     di-(C₁₋₆-alkyl)-amino, di-(C₃₋₆-alkenyl)-amino,     di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl,     C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl,     amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl,     di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl,     C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)amino-C₃₋₆-alkynyl,     hydroxycarbonyl, phenyl, phenyl-C₁₋₃-alkyl, phenyloxy,     phenyl-C₁₋₃-alkoxy, phenyloxy-C₁₋₃-alkyl, phenylcarbonyl, pyridyl,     thiazolyl; pyridylcarbonyl, C₁₋₆-alkyl-carbonyl,     C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl,     C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl,     C₃₋₆-alkynoxy-carbonyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl,     C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl,     di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl,     di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino,     C₁₋₆-alkyl-carbonylamino, C₂₋₆-alkenyl-carbonylamino,     C₂₋₆-alkynyl-carbonylamino, formyl-C₁₋₆-alkyl-amino,     formyl-C₃₋₆-alkenyl-amino, formyl-C₃₋₆-alkynyl-amino,     C₁₋₆-alkyl-carbonyl-C₁₋₆-alkyl-amino,     C₂₋₆-alkenyl-carbonyl-C₁₋₆-alkyl-amino,     C₂₋₆-alkynyl-carbonyl-C₁₋₆-alkyl-amino,     C₁₋₆-alkyl-carbonyl-C₃₋₆-alkenyl-amino,     C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkenyl-amino,     C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkenyl-amino,     C₁₋₆-alkyl-carbonyl-C₃₋₆-alkynyl-amino,     C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkynyl-amino,     C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkynyl-amino, C₁₋₆-alkyl-sulphonyl,     C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl,     C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl,     C₂₋₆-alkynyl-sulphinyl, C₁₋₆-alkyl-sulphonylamino,     C₂₋₆-alkenyl-sulphonylamino, C₂₋₆-alkynyl-sulphonylamino,     C₁₋₆-alkyl-sulphonyl-C₁₋₆-alkylamino,     C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkenylamino,     C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkynylamino,     C₂₋₆-alkenyl-sulphonyl-C₁₋₆-alkylamino,     C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkenyl amino,     C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkynylamino,     C₂₋₆-alkynyl-sulphonyl-C₁₋₆-alkylamino,     C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkenylamino,     C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkynylamino, aminosulphonyl,     C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)aminosulphonyl,     C₃₋₆-alkenylaminosulphonyl, di-(C₃₋₆-alkenyl)-aminosulphonyl,     C₃₋₆-alkynylaminosulphonyl and di-(C₃₋₆-alkynyl)-aminosulphonyl     groups, while the substituents may be identical or different and     wherein any alkyl groups or alkyl sub-moieties optionally are     partially or fully fluorinated, e.g. a CH₃-substituent or methyl     sub-moiety within the substituents mentioned herein is meant to     include the corresponding fluoro-analogs such as the CFH₂—, CF₂H—     and CF₃— group,     and wherein any phenyl, pyridyl and thiazolyl groups or phenyl-,     pyridyl and thiazolyl-submoieties optionally are substituted with 1     or 2 substituents independently of each other selected from     fluorine, chlorine, bromine, iodine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,     C₁₋₃-alkyl-amino, di-(C₁₋₃-alkyl)-amino C₁₋₃-alkylcarbonyl-amino,     C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl-amino, cyano or hydroxy,     and with substituents attached to a nitrogen atom selected from the     group consisting of -   C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclo-C₃₋₇-alkyl,     cyclo-C₃₋₇-alkenyl, cyclo-C₃₋₇-alkyl-C₁₋₆-alkyl, pyrrolidino,     piperidino, morpholino, oxetanyl, tetrahydrofuranyl,     tetrahydropyranyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl,     hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl,     C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl,     C₃₋₆-alkenoxy-C₃₋₆-alkenyl, C₃₋₆-alkenoxy-C₃₋₆-alkynyl,     C₃₋₆-alkynoxy-C₁₋₆-alkyl, C₃₋₆-alkynoxy-C₃₋₆-alkenyl,     C₃₋₆-alkynoxy-C₃₋₆-alkynyl, amino-C₁₋₆-alkyl,     C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl,     amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl,     di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl,     C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl,     hydroxycarbonyl, phenyl, phenyl-C₁₋₆-alkyl, phenylcarbonyl, pyridyl,     pyridylcarbonyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl,     C₂₋₆-alkynyl-carbonyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl,     C₃₋₆-alkynoxy-carbonyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl,     C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl,     di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl,     di-(C₃₋₆-alkynyl)-aminocarbonyl, C₁₋₆-alkyl-sulphonyl,     C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl,     C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl,     C₂₋₆-alkynyl-sulphinyl, aminosulphonyl, C₁₋₆-alkylaminosulphonyl,     di-(C₁₋₆-alkyl)-aminosulphonyl, C₃₋₆-alkenylaminosulphonyl,     di-(C₃₋₆-alkenyl)aminosulphonyl, C₃₋₆-alkynylaminosulphonyl and     di-(C₃₋₆-alkynyl)-aminosulphonyl groups, while the substituents may     be identical or different and wherein any alkyl groups or alkyl     sub-moieties optionally are partially or fully fluorinated, e.g. a     CH₃— substituent or methyl sub-moiety within the substituents     mentioned herein is meant to include the corresponding     fluoro-analogs such as the CFH₂—, CF₂H— and CF₃— group,     and wherein any of the di-(C₁₋₃-alkyl)-amino or     di-(C₁₋₆-alkyl)-amino moieties may form optionally with the nitrogen     atom a 4 to 8 membered ring system,     and wherein any phenyl and pyridyl groups or phenyl- and     pyridyl-submoieties optionally are substituted with 1 or 2     substituents independently of each other selected from fluorine,     chlorine, bromine, iodine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,     C₁₋₃-alkyl-amino, C₁₋₃-alkylcarbonyl-amino, cyano or hydroxy.

The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or “preventive treatment” used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or a CNS-related disorder mentioned herein. Thus the expression “prevention of a disease” as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.

The expression “treatment” or “therapy” means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression “treatment of a disease” as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

PREFERRED EMBODIMENTS OF THE INVENTION

Further preferred embodiments of the invention are characterized by the following definitions:

a) Definitions (a^(i)) for X in the order of preference, ascending from preferably (a¹) to more preferably (a²) up to most preferably (a⁶): (a¹): According to a first preferred embodiment, X is defined as mentioned hereinbefore under the broadest/first embodiment of the invention E-0. (a²): According to a second preferred embodiment,

-   X denotes a divalent 4- to 8-membered monocylic, 7- to 10-membered     spirocyclic or 6- to 12-membered bicyclic saturated, partially or     fully unsaturated group selected from a carbocycle, a     monoaza-heterocycle and a diaza-heterocycle, which is linked to the     adjacent groups via carbon atoms or, if present, via nitrogen atoms,     e.g. via one carbon and one nitrogen atom or via both nitrogen     atoms, -    wherein 1 to 2 —CH₂— groups optionally are replaced independently     of each other by O, S, carbonyl, or sulfonyl, with the proviso that     two heteroatoms are not directly linked together, and/or -    wherein 1 double bond optionally is condensed with an aryl or a 5-     or 6-membered hetaryl group, and/or -    wherein in all groups falling under the above definition of X one     or two carbon atoms optionally and independently are substituted by     halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be     identical or different, and/or, -    wherein one ring member nitrogen atom optionally is substituted by     a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl,     C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or C₁₋₃-alkyl-sulphonyl     group.     (a³): According to a third preferred embodiment, -   X denotes a divalent phenyl group or a group selected from     formulas (II) to (XIII),

-    wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl, or     sulfonyl, with the proviso that two heteroatoms are not directly     linked together, and/or -    wherein a double bond, if present, optionally is condensed with an     aryl or a 5- or 6-membered hetaryl group, and/or -    wherein in all groups falling under the above definition of X one     or two carbon atoms optionally and independently are substituted by     halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy,     hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be     identical or different, and/or, -    wherein one ring member nitrogen atom, if present, optionally is     substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy,     C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or     C₁₋₃-alkyl-sulphonyl group.     (a⁴): According to a fourth preferred embodiment, -   X denotes a divalent phenyl group or a group selected from formulas     (II-XIII) mentioned under embodiment (a³), -    which is linked to the adjacent groups of formula (I) via carbon     atoms or, if present, via nitrogen atoms, e.g. via one carbon and     one nitrogen atom or via both nitrogen atoms, -    wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl, or     sulfonyl, with the proviso that two heteroatoms are not directly     linked together, and/or -    wherein a double bond, if present, optionally is condensed with a     phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,     pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl,     thiazolyl group, and/or -    wherein in all groups falling under the above definition of X one     or two carbon atoms optionally and independently are substituted by     halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,     cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, cyano, hydroxy,     hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be     identical or different, and/or, -    wherein one ring member nitrogen atom, if present, optionally is     substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy,     C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or     C₁₋₃-alkyl-sulphonyl group.     (a⁵): According to a fifth preferred embodiment, -   X denotes a group selected from formulas (II), (III), (VI) or (XIII)     mentioned under embodiment (a³), -    wherein 1 —CH₂— group optionally is replaced independently of each     other by O or carbonyl, -    wherein one or two carbon atoms optionally and independently are     substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano,     hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-amino-carbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be     identical or different.     (a⁶): According to a sixth preferred embodiment, -   X denotes a group selected from formulas (II), (III), (VI), (VII)     or (XIII) mentioned under embodiment (a³), -    wherein 1 —CH₂— group optionally is replaced independently of each     other by O, S, carbonyl, or sulfonyl, with the proviso that two     heteroatoms are not directly linked together, -    wherein one or two carbon atoms optionally and independently are     substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl,     C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano,     hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,     C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl,     C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-amino-carbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be     identical or different, and/or one ring member nitrogen atom is     substituted by C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl,     cyclo-C₃₋₇-alkyl or cyclo-C₃₋₇-alkenyl.     b) Definitions (b^(i)) for Y in the order of preference, ascending     from preferably (b¹) to more preferably (b²) up to most preferably     (b⁷):     (b¹): According to a first preferred embodiment Y is defined as     mentioned hereinbefore under the broadest/first embodiment of the     invention E-0.     (b²): According to a second preferred embodiment, -   Y is absent or denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4,     5 or 6 and wherein 1 —CH₂— group optionally is replaced by O, S,     carbonyl or —NH—, or -    wherein 1 —CH₂— group is replaced by O, S or —NH—, and additionally     a second —CH₂— group is replaced by carbonyl, or -    wherein 1 —CH₂— group is replaced by O, S or —NH—, and additionally     a —CH₂—CH₂— subgroup is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—,     or —NH—C(O)—, and -    wherein any hydrogen atom of the —NH— groups mentioned hereinbefore     optionally and independently is replaced by a C₃₋₆-cycloalkyl or     phenyl group, or by a straight-chained or branched C₁₋₆-alkyl,     phenyl-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl, or C₁₋₆-alkylsulphonyl     group, and/or -    wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally     are replaced by halogen atoms, trifluoromethyl, C₁₋₆-alkyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, phenyl,     phenyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy,     C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₆-alkyl-carbonyl, C₁₋₆-alkoxy-carbonyl,     C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino,     C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or     C₁₋₆-alkyl-sulphonyl groups, while the substituents may be identical     or different, or 2 geminal hydrogen atoms are replaced by a     —(CH₂)_(m)— bridge, wherein m is 2, 3, 4, or 5.     (b³): According to a third preferred embodiment, -   Y is absent or denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4,     5 or 6 and wherein 1 —CH₂— group optionally is replaced by O,     carbonyl or —NH—, or -    wherein 1 —CH₂— group is replaced by O or —NH—, and additionally a     second —CH₂— group is replaced by carbonyl, or -    wherein 1 —CH₂— group is replaced by O and additionally a —CH₂—CH₂—     subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and -    wherein any hydrogen atom of the —NH— groups mentioned hereinbefore     optionally and independently is replaced by a C₃₋₆-cycloalkyl or     phenyl group, or by a straight-chained or branched C₁₋₄-alkyl,     phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, or C₁₋₄-alkylsulphonyl     group, and/or -    wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally     are replaced by halogen atoms, trifluoromethyl, C₁₋₄-alkyl,     C₂₋₄-alkenyl, C₃₋₆-cycloalkyl, phenyl, phenyl-C₁₋₃-alkyl, hydroxy,     hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl,     C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxy-carbonyl, C₁₋₄-alkyl-carbonylamino,     C₁₋₄-alkyl-carbonyl-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-aminocarbonyl, or     di-(C₁₋₃-alkyl)-aminocarbonyl groups, while the substituents may be     identical or different, or 2 geminal hydrogen atoms are replaced by     a —(CH₂)_(m)— bridge, wherein m is 2, 3, 4, or 5.     (b⁴): According to a fourth preferred embodiment, -   Y is absent.     (b⁵): According to a fifth preferred embodiment, -   Y denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4, 5 or 6 and     wherein 1 —CH₂— group optionally is replaced by O, carbonyl or —NH—,     or -    wherein 1 —CH₂— group is replaced by O or —NH—, and additionally a     second —CH₂— group is replaced by carbonyl, or -    wherein 1 —CH₂— group is replaced by O and additionally a —CH₂—CH₂—     subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and -    wherein any hydrogen atom of the —NH— groups mentioned hereinbefore     optionally and independently is replaced by a C₃₋₆-cycloalkyl or     phenyl group, or by a straight-chained or branched C₁₋₄-alkyl,     phenyl-C₁₋₃-alkyl, or C₁₋₃-alkyl-carbonyl, and/or -    wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally     are independently replaced by F, Cl, C₁₋₄-alkyl or trifluoromethyl,     or 1 hydrogen atom attached to a carbon atom optionally is replaced     by C₃₋₆-cycloalkyl, phenyl, phenyl-C₁₋₃-alkyl, hydroxy, or     C₁₋₃-alkoxy groups, while the substituents may be identical or     different, or 2 geminal hydrogen atoms are replaced by a —(CH₂)_(m)—     bridge, wherein m is 2, 3, or 4.     (b⁶): According to a sixth preferred embodiment, -   Y denotes a C₁₋₂-alkyl-linker wherein 1 —CH₂— group optionally is     replaced by O.     (b⁷): According to a seventh preferred embodiment, -   Y denotes a carbonyl group.     c) Definitions (c^(i)) for W in the order of preference, ascending     from preferably (c¹) to more preferably (c²) up to most preferably     (c⁴):     (c¹): According to a first preferred embodiment W is defined as     mentioned hereinbefore under the broadest/first embodiment of the     invention E-0.     (c²): According to a second preferred embodiment, -   W denotes H or an optionally substituted straight-chained or     branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1     or 2 methyl groups optionally are replaced by optionally substituted     phenyl groups or -    an optionally substituted cyclo-C₃₋₉-alkyl group, wherein     independently     -   in a cyclo-C₄₋₇-alkyl group 2 hydrogen atoms attached to         adjacent carbon atoms optionally are replaced to form a double         bond within the ring, which optionally is condensed with an         optionally substituted aryl or an optionally substituted 5- or         6-membered hetaryl group, and the resulting group is bound via a         saturated or unsaturated carbon atom, or     -   in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the         same carbon atom (relative 1,1-position) optionally are replaced         by a C₂₋₅-alkylenyl bridge, or 2 hydrogen atoms attached to         carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally         are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the         resulting polycyclic groups one or two —CH₂— groups optionally         are replaced by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for         replacement of —CH< members), O, or carbonyl, and/or two —CH₂—         groups in relative 1,3-position of a C₄₋₅-alkylenyl bridge         optionally are replaced by O atoms, and/or 2 hydrogen atoms         attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge         optionally are replaced to form a double bond, which optionally         is condensed with an optionally substituted aryl or an         optionally substituted 5- or 6-membered hetaryl group, and/or     -   in a cyclo-C₄₋₈-alkyl group one, two or three ring members         optionally are replaced independently of each other by —NH—,         >N—(C₁₋₆-alkyl), (or N-atoms for replacement of —CH< members),         O, or carbonyl, with the proviso that two heteroatoms are not         directly linked together, and additionally but optionally 2 or 4         hydrogen atoms attached to adjacent ring carbon atoms are         replaced to form a double bond or two conjugated double bonds         within the ring, either of the double bonds optionally being         condensed with an optionally substituted aryl or an optionally         substituted 5- or 6-membered hetaryl group,     -   and any of the resulting groups is bound via a saturated or         unsaturated carbon atom or a nitrogen atom, -    and wherein any of the resulting open-chained or cyclic groups     independently 1 to 3 hydrogen atoms optionally are replaced by     C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or -    any 1 to 6 hydrogen atoms attached to carbon atoms optionally are     replaced by fluorine atoms, -   or W denotes an optionally substituted aryl or hetaryl group, -    an optionally substituted cyclo-C₃₋₈-alkyl-aryl or     cyclo-C₃₋₈-alkyl-hetaryl group, wherein the     cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are     replaced independently of each other by —NH— (or N-atoms for     replacement of —CH< members), O, or carbonyl, with the proviso that     two heteroatoms are not directly linked together, or -   if Y is absent W additionally denotes -    a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, or 5, attached     in relative 1,1-position (geminal) to a carbon atom of group X,     including the options:     -   if p is 3, 4, or 5 it follows that 1 —CH₂— group optionally is         replaced by O, carbonyl, —NH— or —N(C₁₋₆-alkyl), or     -   if p is 4 or 5 it follows that a —CH₂—CH₂— group optionally is         replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl),         —N(C₁₋₆-alkyl)-C(O)—, or —CH═CH—, wherein the double bond         optionally is condensed with an aryl or a 5- or 6-membered         hetaryl group, -    a divalent —(CH₂)_(q)— group, wherein q is 3, or 4 attached in     relative 1,2-position (vicinal) to carbon atoms of group X,     including the options:     -   that 1 —CH₂— group optionally is replaced by O, carbonyl, —NH—         or —N(C₁₋₆-alkyl), or a —CH₂—CH₂— group optionally is replaced         by —O(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl),         —N(C₁₋₆-alkyl)-C(O)—, or     -   that in the resulting 5- or 6-membered carbocyclic ring 2, 4 or,         in case of the 6-membered ring, also 6 hydrogen atoms optionally         are replaced by 1, 2 or 3 bonds to form a partially or fully         unsaturated ring with isolated or conjugated double bonds,         wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl,         —NH— or —N(C₁₋₆-alkyl), and/or one —CH═ unit is replaced by —N═, -    a divalent —(CH₂)₇— group, attached in relative 1,3-position to     carbon atoms as binding sites of group X, including the options:     -   that in the resulting 10-membered carbocyclic ring 2, 4, 6, 8 or         10 hydrogen atoms optionally are replaced by 1, 2, 3, 4 or 5         bonds to form a partially or fully unsaturated ring with         isolated or conjugated double bonds, and/or     -   that in the resulting 10-membered carbocyclic ring 1 hydrogen         atom attached to the carbon atom in position 2 relative to the         binding sites of group X and 1 hydrogen atom attached to a         carbon atom of the —(CH₂)_(r)— group in position 7 relative to         the binding sites of group X optionally are replaced by a bond         (C₀-bridge) to form a bicyclic ring system condensed with the         group X,         -   e.g. X and W together denote the group

wherein any aryl groups or subgroups mentioned above in the definition of W are selected from optionally substituted phenyl, naphthyl, and tetrahydronaphthyl groups, and wherein any hetaryl groups or subgroups mentioned above in the definition of W are selected from optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, indolyl, indolinyl, benzimidazolyl, tetrahydrobenzimidazolyl, tetrahydrocyclopentaimidazolyl, indazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, hexahydrocycloheptapyrazolyl, benztriazolyl, quinolyl, tetrandyroquinolinly, isoquinolyl, tetrandyroisoquinolinly, cinnolyl, quinoxazolyl and benzpyrimidinyl groups, wherein the expression “substituted” or “optionally substituted” as used herein has the same meaning as within embodiment (c¹). (c³): According to a third preferred embodiment,

-   W denotes H or an optionally substituted straight-chained or     branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1     or 2 methyl groups optionally are replaced by optionally substituted     phenyl groups or -    an optionally substituted cyclo-C₃₋₉-alkyl group, wherein     independently     -   in a cyclo-C₄₋₇-alkyl group 2 hydrogen atoms attached to         adjacent carbon atoms optionally are replaced to form a double         bond within the ring, which optionally is condensed with an         optionally substituted aryl or an optionally substituted 5- or         6-membered hetaryl group, and the resulting group is bound via a         saturated or unsaturated carbon atom, or     -   in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the         same carbon atom (relative 1,1-position) optionally are replaced         by a C₂₋₅-alkylenyl bridge, or 2 hydrogen atoms attached to         carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally         are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the         resulting polycyclic groups one or two —CH₂— groups optionally         are replaced by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for         replacement of —CH< members), O, or carbonyl, and/or two —CH₂—         groups in relative 1,3-position of a C₄₋₅-alkylenyl bridge         optionally are replaced by O atoms, and/or 2 hydrogen atoms         attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge         optionally are replaced to form a double bond, which optionally         is condensed with an optionally substituted aryl or an         optionally substituted 5- or 6-membered hetaryl group, and/or     -   in a cyclo-C₄₋₈-alkyl group, two or three ring members         optionally are replaced independently of each other by —NH—,         >N—(C₁₋₆-alkyl), (or N-atoms for replacement of a —CH< members),         O, or carbonyl, with the proviso that two heteroatoms are not         directly linked together, and additionally but optionally 2 or 4         hydrogen atoms attached to adjacent ring carbon atoms are         replaced to form a double bond or two conjugated double bonds         within the ring, either of the double bonds optionally being         condensed with an optionally substituted aryl or an optionally         substituted 5- or 6-membered hetaryl group,     -   and any of the resulting groups is bound via a saturated or         unsaturated carbon atom or a nitrogen atom, -    and wherein any of the resulting open-chained or cyclic groups     independently 1 to 3 hydrogen atoms optionally are replaced by     C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or -    any 1 to 6 hydrogen atoms attached to carbon atoms optionally are     replaced by fluorine atoms, -   or W denotes an optionally substituted aryl or hetaryl group, -    an optionally substituted cyclo-C₃₋₆-alkyl-aryl or     cyclo-C₃₋₆-alkyl-hetaryl group, wherein the     cyclo-C₅₋₆-alkyl-submoieties one or two ring members optionally are     replaced independently of each other by —NH— (or a N-atom for     replacement of a —CH< member), O, or carbonyl, with the proviso that     two heteroatoms are not directly linked together, or -   if Y is absent W additionally denotes -    a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, or 5, attached     in relative 1,1-position (geminal) to a carbon atom of group X,     including the options:     -   if p is 3, 4, or 5 it follows that 1 —CH₂— group optionally is         replaced by O, —NH— or —N(C₁₋₄-alkyl)-, or     -   if p is 4 or 5 it follows that a —CH₂—CH₂— group optionally is         replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₄-alkyl)-,         —N(C₁₋₄-alkyl)-C(O)—, or —CH═CH—, wherein the double bond         optionally is condensed with an aryl or a 5- or 6-membered         hetaryl group, -    a divalent —(CH₂)_(q)— group, wherein q is 3 or 4 attached in     relative 1,2-position (vicinal) to carbon atoms of group X,     including the options:     -   a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—,         —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)-C(O)—, or     -   that in the resulting 5- or 6-membered carbocyclic ring 2, 4 or,         in case of the 6-membered ring, also 6 hydrogen atoms optionally         are replaced by 1, 2 or 3 bonds to form a partially or fully         unsaturated ring with isolated or conjugated double bonds,         wherein 1 —CH₂— group optionally is replaced by O, —NH— or         —N(C₁₋₆-alkyl)-, and/or one —CH═ unit is replaced by —N═, -    the trivalent group

-    attached in relative 1,2,3-position to carbon atoms * as binding     sites of group X,     wherein any aryl groups or aryl-subgroups mentioned above in the     definition of W are selected from optionally substituted phenyl,     naphthyl, and tetrahydronaphthyl groups, and     wherein any hetaryl groups or hetaryl-subgroups mentioned above in     the definition of W are selected from optionally substituted     pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,     triazolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl,     benzthiazolyl, indolyl, indolinyl, benzimidazolyl,     tetrahydrobenzimidazolyl, tetrahydrocyclopentaimidazolyl, indazolyl,     tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,     hexahydrocycloheptapyrazolyl, benztriazolyl, quinolyl,     tetrandyroquinolinly, isoquinolyl, tetrandyroisoquinolinly,     cinnolyl, quinoxazolyl and benzpyrimidinyl groups,     wherein the expression “optionally substituted” means that 1, 2, 3     or 4 hydrogen atoms of the respective group independently are     optionally replaced by substituents selected from fluorine,     chlorine, bromine and iodine atoms, by C₁₋₆-alkyl, trifluoromethyl,     C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl,     cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl,     amino, C₁₋₆-alkyl-amino, (C₁₋₆-alkyl)₂-amino, phenylamino,     N-phenyl-N—(C₁₋₆-alkyl)amino, pyrrolidino, piperidino,     aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, and/or     wherein a hydrogen atom attached to a nitrogen atom, if present in     the respective group, optionally is replaced by a C₁₋₄-alkyl,     C₂₋₄-alkenyl, C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl,     cyclo-C₃₋₇-alkyl-C₁₋₃-alkyl, cyclo-C₃₋₇-alkyl-carbonyl, pyrrolidino,     piperidino, morpholino, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, phenyl,     phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or     C₁₋₃-alkyl-sulphonyl group,     and wherein any phenyl and pyridyl groups or phenyl- and     pyridyl-submoieties optionally are substituted with 1 or 2     substituents independently of each other selected from fluorine,     chlorine, bromine, iodine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,     C₁₋₃-alkyl-amino, C₁₋₃-alkylcarbonyl-amino, cyano or hydroxy.     (c⁴): According to a fourth preferred embodiment, -   W denotes H or an optionally substituted straight-chained or     branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1     or 2 methyl groups optionally are replaced by optionally substituted     phenyl groups or -    an optionally substituted cyclo-C₃₋₈-alkyl group, wherein     independently     -   in a cyclo-C₄₋₈-alkyl group one or two ring members optionally         are replaced independently of each other by —NH—,         >N—(C₁₋₆-alkyl) (or N-atoms for replacement of —CH< members), O,         or carbonyl, with the proviso that two heteroatoms are not         directly linked together, and additionally but optionally 2 or 4         hydrogen atoms attached to adjacent ring carbon atoms are         replaced to form a double bond or two conjugated double bonds         within the ring, either of the double bonds optionally being         condensed with an optionally substituted aryl or an optionally         substituted 5- or 6-membered hetaryl group, and/or     -   in a cyclo-C₄₋₅-alkyl group 2 hydrogen atoms attached to the         same carbon atom (relative 1,1-position) optionally are replaced         by a C₂₋₅-alkylenyl bridge, wherein one —CH₂— group optionally         is replaced by —NH—, >N—(C₁₋₆-alkyl), O, or carbonyl or wherein         two —CH₂— groups in relative 1,3-position of a C₄₋₅-alkylenyl         bridge optionally are replaced O atoms, or wherein a —CH₂—CH₂—         group optionally is replaced by —C(O)—NH—, —NH—C(O)—,         —C(O)—N(C₁₋₆-alkyl)- or —N(C₁₋₆-alkyl)-C(O)— and/or 2 hydrogen         atoms attached to adjacent carbon atoms within a C₄₋₅-alkylenyl         bridge optionally are replaced to form a double bond, which         optionally is condensed with an optionally substituted aryl or         an optionally substituted 5- or 6-membered hetaryl group, or -    an optionally substituted cyclo-C₅₋₉-alkyl group, wherein     independently     -   2 hydrogen atoms attached to carbon atoms in relative 1,2-,         1,3-, 1, 4 or 1,5-position optionally are replaced by a         C₁₋₃-alkylenyl bridge, wherein any of the resulting polycyclic         groups one —CH₂— group optionally is replaced by —NH—,         >N—(C₁₋₆-alkyl), O, or carbonyl, -    wherein any of the resulting groups is bound via a saturated or     unsaturated carbon atom or a nitrogen atom, -    and wherein any of the resulting open-chained or cyclic groups     independently 1 to 3 hydrogen atoms optionally are replaced by     C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or -    any 1 to 6 hydrogen atoms attached to carbon atoms optionally are     replaced by fluorine atoms, -   or W denotes an optionally substituted aryl or hetaryl group, -    an optionally substituted cyclo-C₃₋₆-alkyl-aryl or     cyclo-C₃₋₆-alkyl-hetaryl group, wherein the     cyclo-C₅₋₆-alkyl-submoieties one or two ring members optionally are     replaced independently of each other by —NH— (or a N-atom for     replacement of a —CH< member), O, or carbonyl, with the proviso that     two heteroatoms are not directly linked together, or -   if Y is absent W additionally denotes -    a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, or 5, attached     in relative 1,1-position (geminal) to a carbon atom of group X,     including the options:     -   if p is 4 or 5 it follows that 1 —CH₂— group optionally is         replaced by O, —NH— or —N(C₁₋₄-alkyl)-, or that a —CH₂—CH₂—         group optionally is replaced by —C(O)—NH—, —NH—C(O)—,         —C(O)—N(C₁₋₄-alkyl)-, —N(C₁₋₄-alkyl)-C(O)—, or —CH═CH—, wherein         the double bond optionally is condensed with an aryl or a 5- or         6-membered hetaryl group, -    a divalent —(CH₂)_(q)— group, wherein q is 3 or 4 attached in     relative 1,2-position (vicinal) to carbon atoms of group X,     including the options:     -   a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—,         —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)-C(O)—, or     -   that in the resulting 5- or 6-membered carbocyclic ring 2, 4 or,         in case of the 6-membered ring, also 6 hydrogen atoms optionally         are replaced by 1, 2 or 3 bonds to form a partially or fully         unsaturated ring with isolated or conjugated double bonds,         wherein 1 —CH₂— group optionally is replaced by O, —NH— or         —N(C₁₋₆-alkyl), and/or one —CH═ unit is replaced by —N═, -    the trivalent group

-    attached in relative 1,2,3-position to carbon atoms * as binding     sites of group X,     wherein any aryl groups or aryl-subgroups mentioned above in the     definition of W are selected from optionally substituted phenyl,     naphthyl, and tetrahydronaphthyl groups, and     wherein any hetaryl groups or hetaryl-subgroups mentioned above in     the definition of W are selected from optionally substituted     pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,     triazolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl,     benzthiazolyl, indolyl, indolinyl, benzimidazolyl,     tetrahydrobenzimidazolyl, tetrahydrocyclopentaimidazolyl, indazolyl,     tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,     hexahydrocycloheptapyrazolyl, benztriazolyl, quinolyl,     tetrandyroquinolinly, isoquinolyl, tetrandyroisoquinolinly,     cinnolyl, quinoxazolyl and benzpyrimidinyl groups,     wherein the expression “optionally substituted” means that 1, 2 or 3     hydrogen atoms of the respective group independently are optionally     replaced by substituents selected from     fluorine, chlorine and bromine atoms, atoms, by C₁₋₆-alkyl,     trifluoromethyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl,     cyclo-C₃₋₇-alkenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy,     C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl,     amino, C₁₋₄-alkyl-amino, (C₁₋₄-alkyl)₂-amino, phenylamino,     N-phenyl-N—(C₁₋₄-alkyl)amino, pyrrolidino, piperidino,     aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,     C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,     di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,     formylamino, C₁₋₆-alkyl-carbonylamino,     C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or     C₂₋₆-alkynyl-carbonylamino groups, or     the expression “optionally substituted” means that 4 hydrogen atoms     of the respective group independently are optionally replaced by     substituents selected from fluorine atoms and C₁₋₆-alkyl groups,     and/or     wherein a hydrogen atom attached to a nitrogen atom, if present in     the respective group, optionally is replaced by a C₁₋₄-alkyl,     C₂₋₄-alkenyl, C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl,     cyclo-C₃₋₇-alkyl-C₁₋₃-alkyl, cyclo-C₃₋₇-alkyl-carbonyl, pyrrolidino,     piperidino, morpholino, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, phenyl,     phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or     C₁₋₃-alkyl-sulphonyl group     and wherein any phenyl and pyridyl groups or phenyl- and     pyridyl-submoieties optionally are substituted with 1 or 2     substituents independently of each other selected from fluorine,     chlorine, bromine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino,     C₁₋₃-alkylcarbonyl-amino or hydroxy.     d) Definitions (d^(i)) for R¹, R², R³, R⁴ and R⁵ in the order of     preference, ascending from preferably (d) to more preferably (d²) up     to most preferably (d⁴):     (d¹): According to a first preferred embodiment R¹, R², R³, R⁴ and     R⁵ are defined as mentioned hereinbefore under the broadest/first     embodiment of the invention E-0.     (d²): According to a second preferred embodiment,     R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those     groups being optionally substituted by 1 to 3 fluorine, chlorine or     bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or     cyclo-C₃₋₆-alkyl-group,     R² and R³ independently denote H, halogen, C₁₋₃-alkyl, hydroxy or     C₁₋₃-alkoxy, any of those C₁₋₃-alkyl groups being optionally     substituted by 1 to 3 fluorine atoms,     R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, C₂₋₄-alkenyl,     C₂₋₃-alkynyl, cyclo-C₃₋₆-alkyl, hydroxy or C₁₋₃-alkoxy, any of those     C₁₋₃-alkyl, C₂₋₄-alkenyl or C₂₋₃-alkynyl groups being optionally     substituted by 1 to 3 fluorine atoms, by a methyl, hydroxy,     C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl     group both optionally substituted independently by 1, 2 or 3     substituents selected from     halogen atoms, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, cyano, hydroxy,     C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, and di-(C₁₋₃-alkyl)-amino     groups,     (d³): According to a third preferred embodiment,     R¹ denote H, C₁₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being     optionally substituted by 1 to 3 fluorine or chlorine atoms, or by a     or cyclo-C₃₋₆-alkyl-group,     R² and R³ independently denote H, halogen, C₁₋₃-alkyl, any of those     C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine     atoms,     R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl,     cyclo-C₃₋₆-alkyl, any of those C₁₋₃-alkyl, groups being optionally     substituted by 1 to 3 fluorine atoms, by a methyl, or     cyclo-C₃₋₅-alkyl group, or by a phenyl or pyridyl group, both     optionally substituted independently by 1, 2 or 3 substituents     selected from     halogen atoms, C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, amino, and     C₁₋₃-alkyl-amino groups.     (d⁴): According to a fourth preferred embodiment,     R¹ denote H, C₁₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being     optionally substituted by 1 to 3 fluorine or chlorine atoms, or by a     cyclo-C₃₋₇-alkyl-group,     R² and R³ independently denote H, halogen, or C₁₋₃-alkyl, any of     those C₁₋₃-alkyl groups being optionally substituted by 1 to 3     fluorine atoms,     R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl,     cyclo-C₃₋₅-alkyl, any of those C₁₋₃-alkyl groups being optionally     substituted by 1 to 3 fluorine atoms, by a methyl or     cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group, both     optionally substituted independently by 1, 2 or 3 substituents     selected from     halogen atoms, C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, amino, and     C₁₋₃-alkyl-amino groups.

Each a^(i), b^(i), c^(i), d^(i) represents a characterised, individual embodiment for the corresponding substituent as described above. So given the above definitions, preferred individual embodiments of the first aspect of the invention are fully characterised by the term (a^(i)b^(i)c^(i)d^(i)) if for each letter i in this term an individual figure is given. Indices i vary independently from each other. All individual embodiments described by the term in brackets with full permutation of indices i, referring to the above definitions, shall be comprised by the present invention.

The following table 1 shows, exemplary and in the order of increasing preference from the first line to the last line, such embodiments E-1 to E-15 of the invention that are considered preferred. This means that embodiment E-15, represented by the entries in the last row of table 1 is the most preferred embodiment:

TABLE 1 Preferred embodiments E-1 to E-15 of the invention X Y W R¹, R², R³, R⁴, R⁵ E-1 a¹ b¹ c¹ d² E-2 a² b¹ c¹ d² E-3 a² b² c¹ d² E-4 a² b³ c¹ d² E-5 a³ b³ c² d² E-6 a³ b⁴ c² d² E-7 a³ b⁴ c³ d² E-8 a⁴ b⁴ c³ d² E-9 a⁴ b⁵ c³ d²  E-10 a⁵ b⁵ c³ d²  E-11 a⁵ b⁵ c³ d³  E-12 a⁶ b⁶ c³ d³  E-13 a⁵ b⁶ c⁴ d²  E-14 a⁶ b⁷ c⁴ d³  E-15 a⁶ b⁷ c⁴ d⁴ including the tautomers, the stereoisomers, the mixtures, and the salts thereof.

Particular preferred embodiments of the invention are described in the Examples.

General Routes for Preparation

The compounds of general formula (I) may be prepared by the following methods, for example:

-   (a) In order to prepare compounds of general formula (I) wherein the     group X is linked to the tricyclic core group via a N-atom:     reacting a compound of general formula

wherein R¹, with exception of the hydrogen atom, is defined as hereinbefore or represents a suitable protective group as a protected hydrogen equivalent resulting a hydrogen atom for R¹ after deprotection, preferably benzyl or tert-butoxycarbonyl (boc), R², R³, R⁴ and R⁵ are defined as hereinbefore, and Z¹ denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, with a suitable nitrogen nucleophilic group of formula

wherein X′ denotes the meanings given for X hereinbefore, with the proviso that the H-atom in formula (XV) is attached to a N-atom, and Y and W are defined as mentioned hereinbefore, in a suitable solvent, such as ethanol at suitable temperatures, preferably at a temperature of 40-100° C., and, if necessary, cleaving concurrently or subsequently any protective group used in the reaction described above using standard techniques.

-   (b) In order to prepare compounds of general formula (I) wherein the     group X is linked to the tricyclic core group via a C-atom:     reacting a compound of general formula

wherein R¹, with exception of the hydrogen atom, is defined as hereinbefore or represents a suitable protective group as a protected hydrogen equivalent resulting a hydrogen atom for R¹ after deprotection, preferably benzyl or tert-butoxycarbonyl (boc), R², R³, R⁴ and R⁵ are defined as hereinbefore, and Z¹ denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, with a suitable carbon nucleophilic group of formula

wherein X″ denotes the meanings given for X hereinbefore, with the proviso that the H-atom in formula (XVI) is attached to a C-atom, and Y and W are defined as mentioned hereinbefore, in the presence of a suitable catalyst, such as Pd(0) catalysts, Pd(II) catalysts or Iron (III) catalysts, in a suitable solvent, such as methanol, tetrahydrofurane, dioxane at suitable temperatures, preferably 20° C. up to reflux of the solvent or solvent mixture and, if necessary cleaving concurrently or subsequently any protective group used in the reaction described above using standard techniques. Organo-magnesium reagents, organo-tin reagents, organo-zinc reagents, boronic acid or boronic ester derivatives may be used as carbon nucleophiles. In case the carbon nucleophile represents a boronic acid or a boronic ester, the reaction is carried out in a suitable solvent with a suitable base, such as cesium, sodium or potassium carbonate at suitable temperatures, preferably 20° C. up to reflux of the solvent or solvent mixture.

-   (c) In order to prepare compounds of general formula (I) wherein the     group Y is linked via a carbonyl group to a N-atom of group W:     reacting a compound of general formula

wherein R¹, with exception of the hydrogen atom, is defined as hereinbefore or represents a suitable protective group as a protected hydrogen equivalent resulting a hydrogen atom for R¹ after deprotection, R², R³, R⁴, R⁵ and X are as defined hereinbefore, and Y′ denotes the meanings given for Y hereinbefore, with the proviso that the OH group in formula (XVII) is attached to a carbonyl group, with an amine of formula

H—W′  (XVIII),

wherein W′ denotes the meanings given for W hereinbefore, with the proviso that the H-atom in formula (XVIII) is attached to a N-atom, thus resulting the corresponding amide, and, if necessary cleaving concurrently or subsequently any protective group used in the reaction described above using standard techniques, in case of boc e.g. by treatment with a mixture of dichloromethane and trifluoroacetic acid. The amidation can be carried out using standard procedures including a suitable activation reagent such as EDC, TBTU, PFTU or HATU in a solvent such as DMF and in the presence of a base such as triethyl amine or DIPEA upon treatment with the nucleophilic amine of formula (XVIII).

Compounds of general formula I thus obtained may be resolved into their stereoisomers, if applicable, or converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.

The compounds of general formulas XIV, XV, XVI, XVII and XVIII used as starting or intermediate materials are available as described hereinafter or are either commercially available, known from the literature or may be obtained by methods known from the literature.

The compounds of formula (XIV) are available as follows:

-   (d) Reaction of a compound of formula Prep 1

wherein R¹, R² and R³ are as defined herein, with a compound of formula Prep 2 or its tautomer:

wherein R⁴ and R⁵ are as defined herein, using a suitable solvent, preferably acetic acid at a suitable temperature, preferably 50-100° C., to yield a compound of formula Prep 3 or its tautomer

-   (e) Conversion of a compound of formula Prep 3 into a compound of     formula (XIV) as defined hereinbefore, using a suitable chlorinating     reagent, preferably phosphorus oxychloride, optionally in the     presence of a base, preferably triethyl amine or     ethyldiisopropylamine (DIPEA), at elevated temperature, preferably     40-120° C. In case the protection group is not stable under the     reaction conditions a reprotection (preferably Pg=benzyl or boc)     prior to further reactions may be required.

Compounds of formula (XV), wherein Y denotes an O-atom,

X denotes a divalent 4- to 10-membered monocylic, 7- to 12-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a monoaza-heterocycle and a diaza-heterocycle, and W denotes an optionally substituted aryl or hetaryl group, an optionally substituted cyclo-C₃₋₈-alkyl-aryl or cyclo-C₃₋₈-alkyl-hetaryl group, wherein the cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or a N-atom for replacement of a —CH< member), >N(C₁₋₃-alkyl), O, S, carbonyl, or sulfonyl, are available according to the reaction sequence shown in scheme 1:

wherein X′″ denotes a divalent 4- to 10-membered monocylic, 7- to 12-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a monoaza-heterocycle and a diaza-heterocycle, e.g. an azetidine, pyrrolidine, piperidine or azepine ring, W″ denotes an optionally substituted aryl or hetaryl group, an optionally substituted cyclo-C₃₋₈-alkyl-aryl or cyclo-C₃₋₈-alkyl-hetaryl group, wherein the cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or a N-atom for replacement of a —CH< member), >N(C₁₋₃-alkyl), O, S, carbonyl, or sulfonyl, and Pg represents a suitable protection group attached to a nitrogen atom, resulting a hydrogen atom after deprotection.

In Scheme 1 the hydroxyl group is converted into the corresponding aryl or hetaryl ether by standard techniques using e.g. a Mitsunobu reaction or a nucleophilic substitution. In the latter case the hydroxyl group is transformed into a suitable leaving group such as mesylate or tosylate by standard techniques. The latter intermediates are then dissolved in a suitable solvent such as NMP, DMF or DMA and are treated with the appropriate aryl or hetaryl alcohol together with a suitable base such as cesium, sodium or potassium carbonate to yield Pg-X—O—W. The protection group is removed by standard techniques, in case of boc e.g. by treatment with a mixture of dichloromethane and trifluoroacetic acid.

As already mentioned, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an agonistic activity at the human 5-HT2C receptor. In the literature, compounds which are 5-HT2C receptor ligands are proposed for the treatment of the metabolic syndrome, in particular diabetes type 2, obesity and dyslipidemia.

The biological properties of the new compounds may be investigated as follows:

A stable cell line was generated by transfecting CHO—K1 cells with plasmids containing the human 5-HT2C receptor cDNA (VSV RNA-edited isoform, NM_(—)000868) in expression vector pcDNA3. Transfected cells were maintained in serum-free UltraCHO medium (Bio Whittaker) containing 400 μg/ml G418 at 37° C. in 10% CO₂ atmosphere. The ability of a compound to activate the 5-HT2C receptor was monitored in whole cells by measuring intracellular Ca²⁺ release on a Fluorometric Imaging Plate Reader (FLIPR; Molecular Devices) using the FLIPR Calcium 3 no-wash Assay Kit (Molecular Devices). Cells were seeded overnight in 20 μL UltraCHO medium in black, collagen-coated 384-well plates (Becton Dickinson) at a density of 7.000 cells per well. After 24 h the cells were loaded with the fluorescence dye (Fluo-3) in Hanks buffered salt solution containing 50 mM HEPES and 2.5 mM Probenecid for 80 min at room temperature in the dark. Thereafter, test compound was added in 20 μl Hanks buffered salt solution in the FLIPR. Ca²⁺-release was monitored over 30 sec with a time resolution of 5 sec before the addition of compound and for 90 sec with a 1 sec time resolution after the addition of compound. The fluorescence signal obtained with 1 μM 5-HT as a positive control was set to 100% maximal efficacy (Emax). Data were fitted to a sigmoidal dose-response model using the XLfit4 software (IDBS) and potency of a compound is expressed as EC50 value giving 50% of maximal activation.

The compounds of formula (I) according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of metabolic and CNS-related disorders. More specifically, the compounds of formula (I) are useful for the treatment and/or prevention of disorders involving elevated plasma blood glucose, particularly diabetes mellitus (including Type II or non-insulin dependent diabetes mellitus (NIDDM); Type I or insulin dependent diabetes mellitus (IDDM); and Type III or malnutrition-related diabetes), or of diabetic complications. obesity and dyslipidemia. Furthermore, the compounds of formula (I) are suitable for the treatment and/or prevention of CNS-related disorders such as depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety and epilepsy.

The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include for example those which potentiate the therapeutic effect of a 5-HT2C receptor agonist according to the invention with respect to one of the indications mentioned and/or which allow the dosage of a 5-HT2C receptor agonist according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), SGLT 2 inhibitors (e.g. dapagliflozin, sergliflozin), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g. Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, BI 1356), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. The list also includes inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase and glucokinase activators, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators.

Moreover, therapeutic agents which are suitable for such a combination include active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, SDRIs, axokine, leptin, leptin mimetics, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, 13-blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein-kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.

The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.

Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by modulating 5-HT2C receptor activity. These are preferably metabolic diseases and CNS-related diseases, particularly one of the diseases or conditions listed above, most particularly Type II diabetes or obesity.

The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.

Thus, for example, a pharmaceutical composition according to the invention comprises a combination of a compound of formula I according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin II receptor antagonist optionally together with one or more inert carriers and/or diluents.

The compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.

The Examples that follow are intended to illustrate the present invention without restricting it. The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C.

Experimental Part Definitions

(aq.) aqueous (w/w) Weight:weight ratio DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMA Dimethylacetamide DMF Dimethylformamide EtOAc Ethyl acetate H₂O water KOH Potassium hydroxide MeOH Methanol MgSO₄ Magnesium sulfate Na₂S₂O₃ Sodium thiosulfate Na₂SO₄ Sodium sulfate NMP 1-Methyl-2-pyrrolidon TBME tert-Butyl methyl ether BOP Benzotriazole-1-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate TBTU O-(Benztriazol-1-yl)-N,N,N′,N′,- tetramethyluroniumhexafluoroborat Cs₂CO₃ Caesium Carbonate DME Dimethoxyethane CuI copper(I) iodide TF/TFA Trifluoroacetic acid NaHCO₃ sodium hydrogen carbonate NaH Sodium hydride HCl hydrochloric acid AIBN Azobisisobutyronitrile ^(n)Bu₃SnH Tributyltin hydride THF Tetrahydrofuran

HPLC-Methods Method A:

MET/CR/1278 Standard 3.5 minute method Column Atlantis dC18 2.1 × 50 mm, 5 um Mobile phase A = Formic acid (aq) 0.1% B = Formic acid (acetonitrile) 0.1% Flow rate 1 mL/min Injection volume 3 ul Detector 215 nm (nominal) Gradient Time (mins) % Organic 0 5 2.5 100 2.7 100 2.71 5 3.0 5

Method B:

MET/CR/0990 High pH method Column Zorbax Extend C18 2.1 × 50 mm, 5 um Mobile phase A = 2 mM Amm. Bicarbonate, buffered to pH 10 B = Acetonitrile:2 mM Amm. Bicarbonate 95:5 Flow rate 1 mL/min Injection volume 3 ul Detector 215 nm (nominal) Gradient Time (mins) % Organic 0 1 1.80 100 2.10 100 2.30 1 2.39 1

Method C:

MET/CR/1600 High pH method, high resolution Column Phenomenex Gemini C18 2.0 × 100 mm, 3 um 50 C. Mobile phase A = 2 mM Amm. Bicarbonate, buffered to pH 10 B = Acetonitrile:2 mM Amm. Bicarbonate 95:5 Flow rate 0.5 mL/min Injection volume 3 ul Detector 215 nm (nominal) Gradient Time (mins) % Organic 0 5 5.50 100 5.90 100 5.92 5

Method D:

MET/CR/1673 Generic 2 minutes method Column Atlantis dC18 2.1 × 30 mm, 3 um Mobile phase A = Formic acid (aq) 0.1% B = Formic acid (acetonitrile) 0.1% Flow rate 1 mL/min Injection volume 3 ul Detector 215 nm (nominal) Gradient Time (mins) % Organic 0 5 1.50 100 1.60 100 1.61 5

Method F:

time Vol % water Vol % acetonitrile (min) (incl. 0.1% TFA) (incl. 0.1% TFA) 0 95 5 2 0 100 2.5 0 100 2.6 95 5

Analytical column: Sunfire C18 (Waters); 3.5 μm; 4.6×50 mm; column temperature: 40° C.; flow: 1.5 mL/min; injection volume: 20 μL; detection 210-500 nm

Method G:

time Vol % water Vol % acetonitrile (min) (incl. 0.1% TFA) (incl. 0.1% TFA) 0 95 5 2 0 100 2.49 0 100 2.5 95 5

Analytical column: X-Terra MS C18; 3.5 μm; 4.6×50 mm; column temperature: 40° C.; flow: 1.5 mL/min; injection volume: 20 μL; detection 210-500 nm

Method H:

time Vol % water Vol % acetonitrile (min) (incl. 0.1% TFA) (incl. 0.1% TFA) 0 95 5 2 2 98 2.5 2 98 2.9 95 5

Analytical column: Sunfire C18 (Waters); 3.5 μm; 4.6×50 mm; column temperature: 40° C.; flow: 1.5 mL/min; injection volume: 60 μL; detection 210-500 nm.

Method I:

time Vol % water Vol % acetonitrile (min) (incl. 0.1% TFA) (incl. 0.1% TFA) 0 95 5 2 0 100 3 0 100 5.5 95 5

Analytical column: Sunfire C18 (Waters); 3.5 μm; 4.6×50 mm; column temperature: 40° C.; flow: 1.5 mL/min; injection volume: 20 μL; detection 210-500 nm.

Method J:

time Vol % water Vol % acetonitrile (min) (incl. 0.1% TFA) (incl. 0.1% TFA) 0 95 5 2 2 98 3 2 98 3.4 95 5

Analytical column: Sunfire C18 (Waters); 3.5 μm; 4.6×50 mm; column temperature: 40° C.; flow: 1.5 mL/min; injection volume: 20 μL; detection 210-500 nm.

Method K

Vol % water Vol % acetonitrile time (min) (incl. 0.1% NH₄OH) (incl. 0.1% NH₄OH) 0 95 5 1.8 10 90 2 10 90 2.2 95 5

Analytical column: XBridge (Waters); 2.5 μm; 3×30 mm; column temperature: room temperature; flow: 1.4 mL/min; injection volume: 1 μL; detection 190-400 nm.

Method L

Vol % water Vol % acetonitrile time (min) (incl. 0.1% NH₄OH) (incl. 0.1% NH₄OH) 0 95 5 1.8 10 90 2 10 90 2.2 95 5

Analytical column: XBridge (Waters); 3.5 μm; 4.6×75 mm; column temperature: room temperature; flow: 1.4 mL/min; injection volume: 1 μL; detection 190-400 nm.

Method M

Vol % water Vol % acetonitrile time (min) (incl. 0.1% NH₄OH) (incl. 0.1% NH₄OH) 0 95 5 0.8 10 90 2 10 90 2.2 95 5

Analytical column: XBridge (Waters); 2.5 μm; 3×30 mm; column temperature: room temperature; flow: 1.4 mL/min; injection volume: 1 μL; detection 190-400 nm.

Method N

Vol % water Vol % acetonitrile time (min) (incl. 0.1% formic acid) (incl. 0.1% formic acid) 0 95 5 1 95 5 4 70 30 4.5 10 90 5 10 90 5.5 95 5

Analytical column: Symmetry (Waters); 3.5 μm; 4.6×75 mm; column temperature: room temperature; flow: 1.6 mL/min; injection volume: 5 μL; detection 190-400 nm.

Method O

Vol % water Vol % acetonitrile time (min) (incl. 0.1% formic acid) (incl. 0.1% formic acid) 0 95 5 4.5 5 95 5 5 95 5.5 95 5

Analytical column: Zorbax Stable Bond; 3.5 μm; 4.6×75 mm; column temperature: room temperature; flow: 1.6 mL/min; injection volume: 5 μL; detection 190-400 nm.

Method P

Vol % water Vol % acetonitrile time (min) (incl. 0.1% formic acid) (incl. 0.1% formic acid) 0 95 5 0.1 95 5 1.75 5 95 1.9 5 95 1.95 95 5 2 95 5

Analytical column: Zorbax Stable Bond; 1.8 μm; 3×30 mm; column temperature: room temperature; flow: 1.6 mL/min; injection volume: 5 μL; detection 190-400 nm.

Method Q

Vol % water time (min) (incl. 0.032% NH₄OH) Vol % acetonitrile 0 95 5 2.0 0 100 2.5 0 100 2.6 95 5

Analytical column: XBridge C18 (Waters); 1.7 μm; 2.1×50 mm; column temperature: 60° C.; flow: 1.3 mL/min; injection volume: 1 μL; detection 210-500 nm.

Method R

Vol % water Vol % acetonitrile time (min) (incl. 0.1% HCOOH) (incl. 0.1% HCOOH) 0 95 5 4.5 10 90 5.0 10 90 5.5 95 5

Analytical column: Symmetry C18 (Waters); 3.5 μm; 4.6×75 mm; column temperature: 60° C.; flow: 1.6 mL/min; injection volume: 1 μL; detection 210-500 nm.

Example 1 10-[1,4]Oxazepan-4-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

1a 5-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

To 10.0 g (50.18 mmol) 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 60 mL anhydrous ether maintained between −25° C. and −30° C. were added, over 20 minutes, solutions of 8.2 mL (65.23 mmol) boron trifluoride diethyl etherate in 17 mL anhydrous ether, followed by 6.85 mL (65.23 mmol) ethyl diazoacetate in 17 mL anhydrous ether, and the reaction was maintained between −25° C. and −30° C. for 1 hour. The mixture was allowed to warm to room temperature, 30 mL 30% potassium carbonate solution was added and the mixture extracted with EtOAc (3×30 mL), the organic layers were combined and dried with MgSO₄. After filtration, the solvent was evaporated to give the desired product.

Yield: 14.31 g (100% of theory)

C₁₄H₂₃NO₅ (M=285.34)

predicted: Molecular ion (M+H)⁺: 286 observed: Molecular ion (M+H)⁺: 286

HPLC-MS: 1.92 minutes (Method A)

1b 10-Hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 13.3 g (46.61 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 8 mL acetic acid was added 3.87 g (46.61 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 15 minutes. The resulting solid was collected by filtration and washed with TBME (3×10 mL) to give the desired product.

Yield: 14.18 g (100% of theory)

C₁₅H₂₀N₄O₃ (M=304.35)

predicted: Molecular ion (M+H)⁺: 305 observed: Molecular ion (M+H)⁺: 305

HPLC-MS: 1.43 minutes (Method A)

1c 10-Chloro-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 5 g (16.43 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester was added 15.2 mL (160.8 mmol) of phosphorus oxychloride followed by 2.85 mL (16.43 mmol) of DIPEA. The reaction mixture was stirred at room temperature for 10 minutes, then heated at 90° C. for 1 hour, and allowed to cool to room temperature. 30 mL DCM was added to the mixture and the solid was collected by filtration and washed with DCM (2×10 mL) to give the desired product as a HCl salt.

Yield: 2.24 g (46% of theory)

C₁₀H₁₁ClN₄ (M=222.68)

predicted: Molecular ion (M+H)⁺: 223 observed: Molecular ion (M+H)⁺: 223

HPLC-MS: 0.28 minutes (Method A)

1d 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 2.24 g (8.64 mmol) 10-chloro-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 20 mL DCM was added 3.5 mL (25.12 mmol) of triethylamine followed by 2.41 g (11.06 mmol) di-tert-butyl dicarbonate and the reaction was stirred at room temperature for 2 hours. 10 mL of H₂O was added and the mixture was extracted with DCM (2×20 mL), the organic layers were combined and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 9:1 to 7:3).

Yield: 2.2 g (90% of theory)

C₁₅H₁₉ClN₄O₂ (M=322.80)

predicted: Molecular ion (M+H)⁺: 323/325 observed: Molecular ion (M+H)⁺: 323/325

HPLC-MS: 1.92 minutes (Method A)

Rf: 0.54 (hexane/EtOAc 6:4)

1e 10-[1,4]Oxazepan-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, in a sealed tube in 4 mL ethanol, was added 0.2 mL (1.12 mmol) DIPEA followed by 47 mg (0.34 mmol) homomorpholine hydrochloride, and the reaction was heated at 80° C. for 16 hours. 5 mL of H₂O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 10:0 to 6:4).

Yield: 88 mg (73% of theory)

C₂₀H₂₉N₅O₃ (M=387.49)

predicted: Molecular ion (M+H)⁺: 388 observed: Molecular ion (M+H)⁺: 388

HPLC-MS: 1.85 minutes (Method A)

Rf: 0.4 (hexane/EtOAc 6:4)

1f 10-[1,4]Oxazepan-4-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 88 mg (0.23 mmol) 10-[1,4]oxazepan-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM, was added 1.13 mL (4.5 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated to give the desired product as a HCl salt.

Yield: 52.2 mg (64% of theory)

C₁₅H₂₁N₅O (M=287.37)

predicted: Molecular ion (M+H)⁺: 288 observed: Molecular ion (M+H)⁺: 288

HPLC-MS: 1.18 minutes (Method B)

In case that TF salts are listed a mixture of dichloromethane and TFA (1/1) was used to remove the boc-protection group.

TABLE 1 Yield of final steps or last two Mass steps Salt spec HPLC retention Example Structure (%) type result time (method) 1.1

69 HCl 363 [M + H]⁺ 1.67 (B) 1.2

74 HCl 260 [M + H]⁺ 0.92 (B) 1.3

80 HCl 336 [M + H]⁺ 1.49 (B) 1.4

42 HCl 280 [M + H]⁺ 1.25 (B) 1.5

70 HCl 274 [M + H]⁺ 1.01 (B) 1.6

66 HCl 354 [M + H]⁺ 1.52 (B) 1.7

81 HCl 404 [M + H]⁺ 1.88 (B) 1.8

58 HCl 354 [M + H]⁺ 1.62 (B) 1.9

92 HCl 354 [M + H]⁺ 1.63 (B) 1.10

99 HCl 366 [M + H]⁺ 1.63 (B) 1.11

100 HCl 302 [M + H]⁺ 1.21 (B) 1.12

100 HCl 302 [M + H]⁺ 1.24 (B) 1.13

98 HCl 272 [M + H]⁺ 1.52 (B) 1.14

100 TF 288 [M + H]⁺ 1.78 (C) 1.15

99 TF 334 [M + H]⁺ 4.66 (C) 1.16

38 TF 288.2 [M + H]⁺ 2.26 (G) 1.17

23 TF 326.1 [M + H]⁺ 1.69 (G) 1.18

15 TF 377. 2 [M + H]⁺ 1.46 (G) 1.19

33 TF 378. 3 [M + H]⁺ 1.83 (G) 1.20

33 TF 362.2 [M + H]⁺ 1.78 (G) 1.21

24 TF 364.2 [M + H]⁺ 1.69 (G) 1.22

38 TF 405.3 [M + H]⁺ 1.64 (G) 1.23

7 BS 350.2 [M + H]⁺  1.7 (G) 1.24

30 TF 405.3 [M + H]⁺ 1.61 (G) 1.25

29 TF 378.2 [M + H]⁺ 1.78 (G) 1.26

49 TF 334.2 [M + H]⁺ 1.64 (G) 1.27

47 TF 362.2 [M + H]⁺ 1.76 (G) 1.28

43 TF 385.3 [M + H]⁺ 1.36 (G) 1.29

64 TF 380. 2 [M + H]⁺ 1.87 (G) 1.30

67 TF 380. 2 [M + H]⁺ 1.86 (G) 1.31

69 TF 298.2 [M + H]⁺ 1.53 (G) 1.32

51 TF 328. 2 [M + H]⁺ 1.45 (G) 1.33

75 TF 394.3 [M + H]⁺ 1.95 (G) 1.34

50 TF 320. 2 [M + H]⁺  1.7 (G) 1.35

69 TF 348. 2 [M + H]⁺ 1.79 (G) 1.36

85 TF 288 [M + H]⁺  1.3 (G) 1.37

1 TF 455 [M + H]⁺ 1.97 (G) 1.38

58 TF 2.88 [M + H]⁺ 1.43 (G) 1.39

22 TF 322 [M + H]⁺ 1.62 (G) 1.40

4 TF 426 [M + H]⁺ 1.93 (G) 1.41

36 TF 310.2 [M + H]⁺ 1.35 (H) 1.42

15 TF 388 [M + H]⁺ 1.45 (H) 1.43

23 TF 520. 2 [M + H]⁺ 1.91 (H) 1.44

61 TF 422. 2 [M + H]⁺  1.8 (H) 1.45

73 TF 417. 2 [M + H]⁺ 1.71 (H) 1.46

63 TF 350.2 [M + H]⁺ 1.65 (H) 1.47

24 BS 273 [M + H]⁺ 1.03 (K) 1.48

24 BS 287 [M + H]⁺ 1.61 (L) 1.49

88 TF2 284 [M + H]⁺ 1.55 (J) 1.50

19 TF 356.2 [M + H]⁺ 1.82 (G) 1.51

56 TF 374.2 [M + H]⁺ 1.64 (H) 1.52

39 TF 397.2 [M + H]⁺ 1.43 (H) 1.53

38 TF 374.2 [M + H]⁺ 1.53 (H) 1.54

51 TF 461.2 [M + H]⁺ 1.45 (H) 1.55

57 TF 398.1 [M + H]⁺ 1.61 (H) 1.56

51 TF 400.1 [M + H]⁺ 1.63 (H) 1.57

58 TF 487.2 [M + H]⁺ 1.62 (H) 1.58

39 TF 465.3 [M + H]⁺ 1.73 (H) 1.59

4 BS 377.1 [M + H]⁺ 1.43 (H) 1.60

44 TF 405.2 [M + H]⁺ 1.43 (H) 1.61

28 TF 383.2 [M + H]⁺ 1.38 (H) 1.62

1 TF 329.2 [M + H]⁺ 1.16 (H) 1.63

14 TF 329.2 [M + H]⁺ 1.16 (H) 1.64

24 TF 341.2 [M + H]⁺ 1.33 (H) 1.65

31 TF 397.2 [M + H]⁺ 1.45 (H) 1.66

18 TF 355.2 [M + H]⁺ 1.24 (H) 1.67

3 BS 363.1 [M + H]⁺ 1.37 (H) 1.68

59 TF 388.2 [M + H]⁺ 1.66 (H)

Example 2 10-Azetidin-1-yl-3-bromo-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

2e 10-Azetidin-1-yl-3-bromo-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using route 1, in step b (route 1) 4-bromo-1H-pyrazol-5-amine was used, in step e (route 1) azetidine hydrochloride was used as the amine.

Yield: 80.4 mg (100% of theory)

C₁₃H₁₆BrN₅ (M=322.21)

predicted: Molecular ion (M+H)⁺: 322/324 observed: Molecular ion (M+H)⁺: 322/324

HPLC-MS: 1.36 minutes (Method B)

TABLE 2 HPLC Yield of Mass retention final step Salt spec time Example Structure (%) type result (method) 2.1

79 HCl 414/416 [M + H]⁺ 1.79 (B) 2.2

54 TF 414.1 [M + H]⁺ 1.89 (G)

Example 3 5-Methyl-10-piperidin-1-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

3a 6-Methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

To 2 g (7.01 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (route 1 step a) in 25 mL anhydrous THF at −78° C. was added 9.7 mL (17.46 mmol) of a 1.8 M solution of lithium diisopropylamide in heptane/THF dropwise under an atmosphere of nitrogen. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed up to 0° C. 0.48 mL (7.70 mmol) iodomethane was added at 0° C. and the reaction was left to warm up to room temperature over a period of 2 hours. 100 mL of H₂O was added and the mixture was extracted with EtOAc (3×100 mL), the organic layers were combined, washed with H₂O (2×100 mL) and saturated brine (100 mL) and dried over MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 9:1).

Yield: 1.25 g (60% of theory)

C₁₅H₂₅NO₅ (M=299.37)

predicted: Molecular ion (M+H)⁺: 300 observed: Molecular ion (M+H)⁺: 300

HPLC-MS: 1.98 minutes (Method A)

R_(f): 0.32 (silica, hexane/EtOAc 8:2)

3f 5-Methyl-10-piperidin-1-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 6-methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in route 1 (from step b to step f), in step e (route 1) piperidine was used as the amine.

Yield: 100% of theory

C₁₆H₂₃N₅ (M=285.40)

predicted: Molecular ion (M+H)⁺: 286 observed: Molecular ion (M+H)⁺: 286

HPLC-MS: 1.68 minutes (Method B)

TABLE 3 HPLC Yield of Mass retention final step Salt spec time Example Structure % type result (method) 3.1

98 TF 258 [M + H]⁺ 1.36 (B)

Example 4 10-Azetidin-1-yl-3-bromo-5-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

4f 10-Azetidin-1-yl-3-bromo-5-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using route 3 (step a), route 2 (step a), and route 1 (from step c to step f) with azetidine as the amine in step e (route 1).

Yield: 92% of theory

C₁₄H₁₈BrN₅ (M=336.24)

predicted: Molecular ion (M+H)⁺: 336/338 observed: Molecular ion (M+H)⁺: 336/338

HPLC-MS: 1.59 minutes (Method B)

Example 5 10-Azetidin-1-yl-9-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

5a 5-Oxo-2,5,6,7-tetrahydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

To 4.64 g (16.26 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (route 1 step a) in 200 mL benzene at room temperature was added 1.47 g (8.13 mmol) copper (II) acetate and the resulting reaction mixture was stirred at room temperature for 30 minutes. 7.21 g (16.26 mmol) lead (IV) tetraacetate was added and the reaction was stirred at room temperature for 3 hours. After evaporation of the solvent, the material was partitioned between 250 mL EtOAc and 150 mL H₂O, the organic layer was separated and washed with H₂O (150 mL) and saturated brine (150 mL) and dried over MgSO₄. After filtration and evaporation of the solvent the resulting solid was used for the next step without further purification.

Yield: 3.85 g (crude)

C₁₄H₂₁NO₅ (M=283.33)

predicted: Molecular ion (M+H)⁺: 284 observed: Molecular ion (M+H)⁺: 284

HPLC-MS: 1.88 minutes (Method A)

R_(f): 0.27 (silica, hexane/EtOAc 6:4)

5b 3-Methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

To a suspension of 5.18 g (27.18 mmol) CuI in 85 mL anhydrous THF at −78° C. was added 24 mL (34 mmol) of a 1.4 M solution of methyl magnesium bromide in THF/toluene dropwise under an atmosphere of nitrogen, the reaction was left to warm up to −15° C. and then stirred at this temperature for 45 minutes. It was cooled again at −78° C. and a solution of 3.85 g (13.59 mmol) 5-oxo-2,5,6,7-tetrahydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 30 mL anhydrous THF was added dropwise. The resulting reaction mixture was stirred at −78° C. for 30 minutes and then left to warm up to room temperature over a period of 60 minutes. 100 mL saturated aqueous ammonium chloride was added and the resulting mixture was extracted with EtOAc (3×150 mL), the organic layers were combined, washed with H₂O (2×200 mL) and saturated brine (200 mL) and dried over MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 8:2) to give crude material that was used in the next step.

5c 10-Hydroxy-9-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To a solution of 1.95 g (6.23 mmol) 3-methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 10 mL acetic acid was added 0.52 g (6.23 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 3 hours. After the reaction was cooled at room temperature, the solvent was evaporated and the product purified by column chromatography (silica, DCM/MeOH 95:5).

Yield: 1.98 g (38% of theory for three steps)

C₁₆H₂₂N₄O₃ (M=318.38)

predicted: Molecular ion (M+H)⁺: 319 observed: Molecular ion (M+H)⁺: 319

HPLC-MS: 1.54 minutes (Method A)

R_(f): 0.42 (silica, DCM/MeOH 9:1)

5g 10-Azetidin-1-yl-9-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-hydroxy-9-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (from step c to f), in step e (route 1) azetidine was used as the amine.

Yield: 100% of theory

C₁₄H₁₉N₅ (M=257.34)

predicted: Molecular ion (M+H)⁺: 258 observed: Molecular ion (M+H)⁺: 258

HPLC-MS: 1.23 minutes (Method B)

Example 6 10-Azetidin-1-yl-3-(2-pyridin-2-yl-ethyl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

6a 10-Chloro-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, step a to d) in 2 mL DMF, under nitrogen, was added 0.104 g (0.46 mmol) N-iodosuccinimide, and the reaction was stirred at room temperature for 16 hours. 20 mL EtOAc was added and the mixture was washed with a 10% solution of Na₂S₂O₃ (2×5 mL). The aqueous layers were combined and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10 mL saturated brine, and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1).

Yield: 139 mg (100% of theory)

C₁₅H₁₈ClIN₄O₂ (M=448.69)

predicted: Molecular ion (M+H)⁺: 449/451 observed: Molecular ion (M+H)⁺: 449/451

HPLC-MS: 2.25 minutes (Method A)

R_(f): 0.46 (heptane/EtOAc 7:3)

6b 10-Azetidin-1-yl-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

The product was prepared using 10-chloro-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester and azetidine as the amine in route 1 (step e).

Yield: 0.35 g (98% crude)

C₁₈H₂₄IN₅O₂ (M=469.33)

predicted: Molecular ion (M+H)⁺: 470 observed: Molecular ion (M+H)⁺: 470

HPLC-MS: 1.27 minutes (Method A)

6c 10-Azetidin-1-yl-3-pyridin-2-ylethynyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 0.1 g (0.21 mmol) 10-azetidin-1-yl-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in a sealed tube under nitrogen was added 3 mL of dioxane and the mixture was degassed with nitrogen for 3 minutes. 14.7 mg (0.02 mmol) 1,1′-bis-(diphenylphosphino)-ferrocenedichloro palladium (II) was added and the reaction mixture was stirred at room temperature for 30 minutes. 86 μL (0.85 mmol) 2-ethynyl pyridine was added followed by 0.53 mL (3.8 mmol) triethylamine and 4 mg (0.02 mmol) CuI, and the reaction was stirred at 60° C. for 16 hours under nitrogen. The mixture was cooled to room temperature and partitioned between 20 mL EtOAc and 20 mL saturated ammonium chloride. The mixture was extracted with EtOAc (3×10 mL), the organic layers combined, washed with 20 mL brine, and dried with MgSO₄. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 3:7).

Yield: 87 mg (92% of theory)

C₂₅H₂₈N₆O₂ (M=444.54)

predicted: Molecular ion (M+H)⁺: 445 observed: Molecular ion (M+H)⁺: 445

HPLC-MS: 1.28 minutes (Method A)

6d 10-Azetidin-1-yl-3-(2-pyridin-2-yl-ethyl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 87 mg (0.2 mmol) 10-azetidin-1-yl-3-pyridin-2-ylethynyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL ethanol was added 11 mg (20% weight) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at room temperature under a balloon of hydrogen for 16 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 3:7).

Yield: 71 mg (81% of theory)

C₂₅H₃₂N₆O₂ (M=448.57)

predicted: Molecular ion (M+H)⁺: 449 observed: Molecular ion (M+H)⁺: 449

HPLC-MS: 0.95 minutes (Method D)

6e 10-Azetidin-1-yl-3-(2-pyridin-2-yl-ethyl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-azetidin-1-yl-3-(2-pyridin-2-yl-ethyl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step f).

Yield: 60.1 mg (90% of theory)

C₂₀H₂₄N₆ (M=348.45)

predicted: Molecular ion (M+H)⁺: 349 observed: Molecular ion (M+H)⁺: 349

HPLC-MS: 3.75 minutes (Method C)

TABLE 4 HPLC Yield of Mass retention final Salt spec time Example Structure step % type result (method) 6.1

22 none 312 [M + H]⁺ 4.60 (C)

Example 7 10-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

7a 5-Oxo-azepane-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester

To 1.0 g (4.28 mmol) 4-oxo-piperidine-1-carboxylic acid benzyl ester in 5 mL anhydrous ether maintained between −25° C. and −30° C. were added, over 20 minutes, solutions of 0.7 mL (5.56 mmol) BF₃Et₂O in 1.5 mL anhydrous ether, followed by 0.67 mL (6.42 mmol) ethyl diazoacetate in 1.5 mL anhydrous ether, and the reaction was maintained between −25° C. and −30° C. for 1 hour. The mixture was allowed to warm up to room temperature, 10 mL 30% potassium carbonate solution was added and the mixture extracted with EtOAc (3×15 mL), the organic layers were combined and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by flash column chromatography (silica, hexane/EtOAc 9:1 to 8:2).

Yield: 1.1 g (80% of theory)

C₁₇H₂₁NO₅ (M=319.36)

predicted: Molecular ion (M+H)⁺: 320 observed: Molecular ion (M+H)⁺: 320

HPLC-MS: 1.97 minutes (Method A)

R_(f): 0.35 (hexane/EtOAc 7:3)

7b 10-Hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester

To 5.87 g (18.38 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester in 3 mL acetic acid was added 1.53 g (18.38 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 15 minutes. The resulting solid was collected by filtration and washed with TBME (3×10 mL) to give the desired product.

Yield: 5.9 g (95% of theory)

C₁₈H₁₈N₄O₃ (M=338.37)

predicted: Molecular ion (M+H)⁺: 339 observed: Molecular ion (M+H)⁺: 339

HPLC-MS: 1.5 minutes (Method A)

7c 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester

To a suspension of 3.0 g (8.86 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 6 mL toluene was added 7 mL (74.06 mmol) of phosphorus oxychloride and 1.28 mL (7.35 mmol) of DIPEA, and the reaction was heated at reflux for 40 minutes. The mixture was cooled to room temperature and poured into ice. The aqueous phase was extracted with DCM (3×20 mL) and the combined organic layers were dried over MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 7:3).

Yield: 2.0 g (63% of theory)

C₁₈H₁₇ClN₄O₂ (M=356.81)

predicted: Molecular ion (M+H)⁺: 357/359 observed: Molecular ion (M+H)⁺: 357/359

HPLC-MS: 1.99 minutes (Method A)

R_(f): 0.4 (heptane/EtOAc 7:3)

7d 10-Morpholin-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester

To 0.15 g 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester (0.42 mmol), in a sealed tube in 8 mL ethanol, was added 78 μL (0.88 mmol) morpholine, and the reaction was heated at 60° C. for 16 hours. 5 mL of H₂O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 2%).

Yield: 0.15 g (88% of theory)

C₂₂H₂₅N₅O₃ (M=407.48)

predicted: Molecular ion (M+H)⁺: 408 observed: Molecular ion (M+H)⁺: 408

HPLC-MS: 1.88 minutes (Method A)

7e 10-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 0.15 g (0.37 mmol) 10-morpholin-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid benzyl ester in 8 mL ethanol was added 30 mg (20% weight) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at room temperature under a balloon of hydrogen for 4 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite and the solvent was evaporated to give the desired product.

Yield: 96 mg (95% of theory)

C₁₄H₁₉N₅O (M=273.34)

predicted: Molecular ion (M+H)⁺: 274 observed: Molecular ion (M+H)⁺: 274

HPLC-MS: 1.08 minutes (Method B)

TABLE 5 Yield of final Mass spec HPLC retention Example Structure step (%) result time (method) 7.1

100 258 [M + H]⁺ 1.29 (B) 7.2

 98 272 [M + H]⁺ 1.44 (B) 7.3

 41 417 [M + H]⁺ 1.94 (B) 7.4

 89 244 [M + H]⁺ 1.39 (B) 7.5

 82 286 [M + H]⁺ 1.71 (B)

Example 8 (S)-10-(2-Methoxymethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

8a (S)-2-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester

To 699 mg (18.48 mmol) sodium borohydride in 20 mL dry THF under nitrogen, was added 1.15 g (5.74 mmol) (S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester and the reaction was cooled to 0° C., 1.72 g (6.78 mmol) iodine in 10 mL dry THF was added dropwise over 30 minutes, the reaction mixture was allowed to warm to room temperature, and was heated under reflux for 19 hours. The mixture was cooled to room temperature and 25 mL MeOH was added dropwise over 15 minutes. After evaporation of the solvent, 30 mL KOH (1 M) was added and the mixture was stirred at room temperature for 2 hours. The aqueous phase was extracted with DCM (2×75 mL) and the combined organic layers were washed with saturated brine (3×50 mL), then dried over MgSO₄. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.

8b (S)-Azetidin-2-yl-methanol hydrogen chloride

To 756.2 mg (4.04 mmol) (S)-2-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 3 mL DCM was added 2 mL (8 mmol) HCl in dioxane (4 M) and the reaction was stirred at room temperature for 5 hours. The solvent evaporated to give the desired product as a HCl salt, which was used for the next step without further purification.

8c (S)-10-(2-Hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylicacid tert-butyl ester

To 50 mg (0.155 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, from step a to d) and 22 mg (0.17 mmol) (S)-azetidin-2-yl-methanol hydrogen chloride in 2 mL ethanol was added 2 mL (0.31 mmol) DIPEA, and the reaction mixture was heated at 80° C. for 19 hours. The reaction was cooled to room temperature and 20 mL EtOAc was added. The organic layer was washed with 10 mL citric acid (1 M), H₂O (2×10 mL), 10 mL saturated brine, and dried over MgSO₄. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 1:5).

Yield: 25.33 mg (44% of theory)

C₁₉H₂₇N₅O₃ (M=373.46)

predicted: Molecular ion (M+H)⁺: 374 observed: Molecular ion (M+H)⁺: 374

HPLC-MS: 1.26 minutes (Method A)

8d (S)-10-(2-Methoxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 57.9 mg (0.155 mmol) (S)-10-(2-hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF was added 29.8 mg (1.24 mmol, 60% dispersion in mineral oil) NaH and the reaction was cooled to 0° C. 0.4 mL (1.24 mmol) methyl iodide was added and the reaction was stirred at room temperature for 6 hours. 25 mL EtOAc was added and the organic layer was washed with H₂O (2×20 mL), 20 mL saturated brine, and dried over MgSO₄. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 2:3).

Yield: 60.1 mg (100% of theory)

C₂₀H₂₉N₅O₃ (M=387.49)

predicted: Molecular ion (M+H)⁺: 388 observed: Molecular ion (M+H)⁺: 388

HPLC-MS: 1.41 minutes (Method A)

R^(f): 0.25 (heptane/EtOAc 2:3)

8e (S)-10-(2-Methoxymethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 60.1 mg (0.155 mmol) (S)-10-(2-methoxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM was added 2 mL (3.1 mmol) HCl in dioxane (4 M) and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a HCl salt.

Yield: 48.8 mg (87% of theory)

C₁₅H₂₁N₅O (M=287.37)

predicted: Molecular ion (M+H)⁺: 288 observed: Molecular ion (M+H)⁺: 288

HPLC-MS: 1.37 minutes (Method B)

TABLE 6 HPLC Yield of Mass retention final step Salt spec time Example Structure (%) type result (method) 8.1

59 HCl 288 [M + H]⁺ 1.35 (B) 8.2

42 TF 274 [M + H]⁺ 0.98 (B)

Example 9 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

9a 3-Dimethylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester

To 300 mg (1.49 mmol) azetidine-1,3-dicarboxylic acid mono-tert-butyl ester and 241.6 mg (1.79 mmol) 1-hydroxybenzotriazole hydrate in 20 mL DMF at 0° C., was added 364.5 mg (4.47 mmol) dimethylamine hydrochloride, and the reaction was stirred for 30 minutes. 342.8 mg (1.79 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, followed by 1.5 mL (8.94 mmol) DIPEA were added, and the reaction was stirred at room temperature for 3 hours. After evaporation of the solvent, the crude was diluted with 100 mL DCM. The organic phase was washed with a 2 M solution of HCl (2×50 mL), a saturated solution of NaHCO₃ (2×50 mL), brine (2×50 mL), and dried over Na₂SO₄. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.

9b Azetidine-3-carboxylic acid dimethylamide trifluoroacetate

To 324.3 mg (1.42 mmol) 3-dimethylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 7.5 mL DCM was added 2.5 mL TFA and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a TFA salt, which was used for the next step without further purification.

9d 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

The product was prepared by using route 1 (step e and f) using azetidine-3-carboxylic acid dimethylamide trifluoroacetate as the amine in step e (route 1).

Yield: 33% of theory

C₁₆H₂₂N₆O (M=314.39)

predicted: Molecular ion (M+H)⁺: 315 observed: Molecular ion (M+H)⁺: 315

HPLC-MS: 1.19 minutes (Method B)

TABLE 7 Yield of final HPLC step Salt Mass spec retention time Example Structure (%) type result (method) 9.1

9 base 301 [M + H]⁺ 1.07 (B)

Example 10 10-[3-(5-Methyl-oxazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

10a 3-Prop-2-ynylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester

To 0.5 g (2.48 mmol) boc-azetidine-3-carboxylic acid in 5 mL DCM were added 0.52 g (2.73 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.4 g (2.98 mmol) 1-hydroxybenzotriazole hydrate and 0.9 mL (5.47 mmol) DIPEA, and the reaction was stirred at room temperature for 30 minutes. 0.19 mL (2.73 mmol) propargylamine was added and the reaction was stirred for 16 hours at room temperature. 5 mL DCM was added and the mixture was washed with 10 mL aqueous HCl (1 M), then 10 mL aqueous NaHCO₃ (1 M) and 10 mL brine. The organic layer was dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3).

Yield: 0.334 g (57% of theory)

C₁₂H₁₈N₂O₃ (M=238.29)

predicted: Molecular ion (M+H)⁺: 239 observed: Molecular ion (M+H)⁺: 239

HPLC-MS: 1.53 minutes (Method A)

10b 3-(5-Methyl-oxazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

To 0.22 g (0.92 mmol) 3-prop-2-ynylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 4 mL anhydrous acetonitrile, under nitrogen, was added 14 mg (0.046 mmol) gold (III) chloride and the reaction mixture was stirred at 45° C. for 6 hours. After evaporation of the solvent, 20 mL DCM was added, the organic layer was washed with H₂O (2×10 mL) then dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 6:4 to 5:5), and used for the next step without further purification.

10c 2-Azetidin-3-yl-5-methyl-oxazole hydrochloride

To 57 mg (0.24 mmol) 3-(5-methyl-oxazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL (8 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a HCl salt, which was used for the next step without further purification.

10e 10-[3-(5-Methyl-oxazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]indene

The product was prepared using route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-5-methyl-oxazole hydrochloride was used as the amine.

Yield: 77.3 mg (90% of theory)

C₁₇H₂₀N₆O (M=324.39)

predicted: Molecular ion (M+H)⁺: 325 observed: Molecular ion (M+H)⁺: 325

HPLC-MS: 3.49 minutes (Method C)

Example 11 10-[3-(4-Methyl-thiazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

11a 3-Carbamoyl-azetidine-1-carboxylic acid tert-butyl ester

To 1.0 g (4.97 mmol) boc-azetidine-3-carboxylic acid in 10 mL anhydrous THF was added 0.55 mL of 1-methyl-2-pyrrolidinone. The reaction mixture was cooled to −20° C., then 0.62 mL (4.72 mmol) isobutyl chloroformate was added and the reaction was stirred for 5 minutes. 1.51 mL (24.85 mmol) aqueous ammonia (28% w/w) was added and the mixture was stirred at −20° C. for 2 hours. 5 mL aqueous NaHCO₃ (1 M) was added and the mixture was allowed to reach room temperature over 1 hour. The mixture was extracted with DCM (3×10 mL), the organic layers were combined, washed with aqueous NaHCO₃ (1 M), aqueous citric acid (1 M) and dried over Na₂SO₄. After filtration and evaporation of the solvent the product was used in the next step without further purification.

Yield: 740 mg (74% crude)

11b 3-Thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester

To 0.35 g (1.75 mmol) 3-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 3.5 mL DCM was added 0.39 g (0.96 mmol) Laweson's reagent and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the product was purified twice by column chromatography (silica, heptane/EtOAc 8:2 to 5:5; silica, heptane/EtOAc 7:3 to 6.5:3.5).

Yield: 195 mg (52% of theory)

C₉H₁₆N₂O₂S (M=216.30)

predicted: Molecular ion (M+H)⁺: 217 observed: Molecular ion (M+H)⁺: 217

HPLC-MS: 1.59 minutes (Method A)

11c 3-(4-Methyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

To 145 mg (0.67 mmol) 3-thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 3 mL MeOH in a sealed tube was added 64 μL (0.8 mmol) chloroacetone, and the reaction was stirred at 90° C. for 3 hours. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 8:2 to 6:4).

Yield: 35 mg (21% of theory)

C₁₂H₁₈N₂O₂S (M=254.35)

predicted: Molecular ion (M+H)⁺: 255 observed: Molecular ion (M+H)⁺: 255

HPLC-MS: 1.91 minutes (Method A)

11d 2-Azetidin-3-yl-4-methyl-thiazole hydrochloride

To 47 mg (0.18 mmol) 3-(4-methyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL (8 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a HCl salt, which was used in the next step without further purification.

11f 10-[3-(4-Methyl-thiazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]indene

The product was prepared using route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-4-methyl-thiazole hydrochloride was used as the amine.

Yield: 66.4 mg (83% of theory)

C₁₇H₂₀N₆S (M=340.45)

predicted: Molecular ion (M+H)⁺: 341 observed: Molecular ion (M+H)⁺: 341

HPLC-MS: 3.69 minutes (Method C)

Example 12 10-(3-Benzothiazol-2-yl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

12a 3-Benzothiazol-2-yl-azetidine-1-carboxylic acid tert-butyl ester

To 10 mL DCE was added 533 mg (3.7 mmol) phosphorus pentoxide and 1.57 mL (7.36 mmol) bis-trimethylsilyl ether and the mixture was heated at 80° C. for 15 minutes. 0.19 g (0.92 mmol) N-boc-azetidine-3-carboxylic acid and 108 μL (1.01 mmol) 2-aminothiophenol were added and the mixture heated at 85° C. for 20 minutes. After cooling to room temperature the mixture was diluted with 20 mL DCM and washed with 1 M Na₂CO₃ (2×10 mL). The organic layer was dried with Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 1:1).

Yield: 30 mg (11% of theory)

C₁₅H₁₈N₂O₂S (M=290.39)

predicted: Molecular ion (M+H)⁺: 291 observed: Molecular ion (M+H)⁺: 291

HPLC-MS: 1.49 minutes (Method A)

Rf: 0.50 (EtOAc)

12b 3-Benzothiazol-2-yl-azetidine trifluoroacetate

To 48 mg (166 mmol) 3-benzothiazol-2-yl-azetidine-1-carboxylic acid tert-butyl ester was added 5 mL DCM and 5 mL TFA. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the product as the TFA salt which was used in the next step without further purification.

12c 10-(3-Benzothiazol-2-yl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 3-benzothiazol-2-yl-azetidine trifluoroacetate was used as the amine.

Yield: 68 mg (64% of theory)

C₂₀H₂₀N₆S (M=376.49)

predicted: Molecular ion (M+H)⁺: 377 observed: Molecular ion (M+H)⁺: 377

HPLC-MS: 4.27 minutes (Method C)

Example 13 10-[3-(4-Methyl-oxazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

13a Azetidine-1,3-dicarboxylic acid monobenzyl ester

To 500 mg (4.95 mmol) azetidine-3-carboxylic acid was added 10 mL dioxane and 10 mL H₂O and the solution cooled to 0° C. 1.38 g (10 mmol) potassium carbonate was added followed by 0.78 mL (11 mmol) benzylchloroformate, and the reaction stirred at room temperature for 18 hours. The mixture was acidified with 25 mL 1 M HCl, extracted with DCM (2×20 mL), the combined organic layers dried over Na₂SO₄. After filtration the solvent was evaporated to give the desired product which was used in the next step without further purification.

C₁₂H₁₃NO₄ (M=235.24)

predicted: Molecular ion (M+H)⁺: 236 observed: Molecular ion (M+H)⁺: 236

HPLC-MS: 1.14 minutes (Method A)

13b Azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl) ester

To 321 mg (75% w/w, 1.37 mmol) azetidine-1,3-dicarboxylic acid monobenzyl ester in 10 mL dry THF were added 82 mg NaH (2.05 mmol, 60% dispersion in mineral oil), 182 mg 18-crown-6 (0.68 mmol), 328 μL chloroacetone (4.11 mmol), and the mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, 10 mL 1 M sodium bicarbonate was added and the mixture was extracted with DCM (2×10 mL), the organic layers were combined and dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane-EtOAc 1:1 to EtOAc).

Yield: 204 mg (51% of theory)

C₁₅H₁₇NO₅ (M=291.31)

predicted: Molecular ion (M+H)⁺: 292 observed: Molecular ion (M+H)⁺: 292

HPLC-MS: 1.14 minutes (Method A)

13c 3-(4-Methyl-oxazol-2-yl)-azetidine-1-carboxylic acid benzyl ester

To 130 mg (0.45 mmol) azetidine-1,3-dicarboxylic acid 1-benzyl ester 3-(2-oxo-propyl) ester in 4 mL xylene were added 132 mg (2.25 mmol) acetamide, 39 μL (0.31 mmol) boron trifluoride etherate and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature and evaporation of the solvent the product was purified by chromatography (silica, hexane-EtOAc 6:4).

Yield: 19 mg (15% of theory)

C₁₅H₁₆N₂O₃ (M=272.31)

predicted: Molecular ion (M+H)⁺: 273 observed: Molecular ion (M+H)⁺: 273

HPLC-MS: 1.30 minutes (Method A)

13d 2-Azetidin-3-yl-4-methyl-oxazole

To 40 mg (0.15 mmol) 3-(4-methyl-oxazol-2-yl)-azetidine-1-carboxylic acid benzyl ester in 2 mL ethanol was added 4 mg (20% w/w on carbon) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at 30° C. under a balloon of hydrogen for 18 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite. The solvent was evaporated to give the desired product, which was used in the next step without further purification.

13e 10-[3-(4-Methyl-oxazol-2-yl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-4-methyl-oxazole was used as the amine.

Yield: 4.8 mg (15% of theory)

C₁₇H₂₀N₆O (M=324.39)

predicted: Molecular ion (M+H)⁺: 325 observed: Molecular ion (M+H)⁺: 325

HPLC-MS: 3.41 minutes (Method C)

Example 14 10-(3-Benzooxazol-2-yl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

14a 3-(2-Iodo-phenylcarbamoyl)-azetidine-1-carboxylic acid benzyl ester

To 1.0 g (4.57 mmol) iodoaniline in 30 mL acetonitrile were added 2.22 g (5.02 mmol) BOP, 1.78 g (4.57 mmol) azetidine-1,3-dicarboxylic acid monobenzyl ester (route 13, step a), 0.6 mL (4.57 mmol) triethylamine, and the mixture was stirred at room temperature for 16 hours. 0.6 mL (4.57 mmol) triethylamine was added and the mixture was stirred for 2 hours. 2.22 g (5.02 mmol) BOP was added and the mixture was stirred at room temperature for 16 hours. 30 mL 1 M aqueous Na₂CO₃ was added and the mixture was extracted with EtOAc (2×30 mL), the organic layers were combined, washed with 30 mL brine then dried with Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3).

Yield: 0.47 g (24% of theory)

C₁₈H₁₇IN₂O₃ (M=436.25)

predicted: Molecular ion (M+H)⁺: 437 observed: Molecular ion (M+H)⁺: 437

HPLC-MS: 1.39 minutes (Method D)

14b 3-Benzooxazol-2-yl-azetidine-1-carboxylic acid benzyl ester

To 195 mg (0.45 mmol) 3-(2-iodo-phenylcarbamoyl)-azetidine-1-carboxylic acid benzyl ester in 4.5 mL DME in a sealed tube under nitrogen were added 291 mg (0.89 mmol) Cs₂CO₃, 8.1 mg (44.6 μmol) 1,10-phenanthroline, 4.3 mg (22.3 μmol) CuI, and the mixture was heated at 90° C. for 16 hours. After cooling to room temperature, 5 mL H₂O was added followed by 4 drops 1 M HCl, 5 mL NaHCO₃ and the mixture was extracted with DCM (3×10 mL). The organic layers were combined and dried with Na₂SO₄. After filtration and evaporation of the solvent the product was purified by preparative HPLC.

Yield: 67 mg (49% of theory)

C₁₈H₁₆N₂O₃ (M=308.34)

predicted: Molecular ion (M+H)⁺: 309 observed: Molecular ion (M+H)⁺: 309

HPLC-MS: 1.42 minutes (Method D)

14c 2-Azetidin-3-yl-benzooxazole

The product was prepared using 3-benzooxazol-2-yl-azetidine-1-carboxylic acid benzyl ester in route 13 (step d).

Yield: 100% crude yield

C₁₀H₁₀N₂O (M=174.20)

predicted: Molecular ion (M+H)⁺: 175 observed: Molecular ion (M+H)⁺: 175

HPLC-MS: 0.22 minutes (Method A)

14e 10-(3-Benzooxazol-2-yl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-yl-benzooxazole was used as the amine.

Yield: 66 mg (37% of theory)

C₂₀H₂₀N₆O (M=360.42)

predicted: Molecular ion (M+H)⁺: 361 observed: Molecular ion (M+H)⁺: 361

HPLC-MS: 1.28 minutes (Method C)

Example 15 10-[3-(4-Fluoro-phenoxymethyl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

15a 3-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of 0.56 g (14.91 mmol) sodium borohydride in 10 mL THF was added 1.0 g (4.97 mmol) 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid, and the reaction mixture was cooled to 0° C. 1.26 g (4.97 mmol) iodine in 5 mL THF was added dropwise over 15 minutes and the reaction was stirred at 0° C. for 10 minutes, then heated under reflux for 18 hours. The mixture was allowed to cool to room temperature, diluted with 80 mL MeOH and stirred until all effervescence ceased. After evaporation of the solvent, 25 mL 20% (w/w) KOH was added to the residue and the mixture was stirred for 4.5 hours. The mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over MgSO₄. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.

Yield: 0.84 g (90% of theory)

C₉H₁₇NO₃ (M=187.24)

predicted: Molecular ion (M+H—CH₂═C(CH₃)₂)⁺: 132 observed: Molecular ion (M+H—CH₂═C(CH₃)₂)⁺: 132

HPLC-MS: 1.34 minutes (Method A)

15b 10-(3-Hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

A mixture of 2.57 g (13.75 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester and 2.62 g (13.75 mmol) para-toluenesulfonic acid monohydrate in 14 mL DCM was stirred at room temperature for 16 hours. After evaporation of the solvent, the residue was dissolved in 28 mL EtOH, then 4.8 mL (27.5 mmol) DIPEA followed by 4.03 g (12.5 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester were added and the reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature and the solvent was evaporated. 300 mL DCM was added to the mixture, the organic layer was washed sequentially with 100 mL saturated solution of NaHCO₃, a mixture of 1.94 g (9.23 mmol) citric acid monohydrate in 100 mL H₂O and 100 mL saturated brine, then was dried over MgSO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (Biotage silica 40+M, heptane/EtOAc 1:1 to EtOAc).

Yield: 2.59 g (56% of theory)

C₁₉H₂₇N₅O₃ (M=373.46)

predicted: Molecular ion (M+H)⁺: 374 observed: Molecular ion (M+H)⁺: 374

HPLC-MS: 1.20 minutes (Method A)

15c 10-[3-(4-Fluoro-phenoxymethyl)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 0.1 g (0.268 mmol) 10-(3-hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 0.3 mL THF, was added 30 mg (0.268 mmol) 4-fluorophenol followed by 74 mg (0.281 mmol) triphenylphospine and the reaction mixture was sonicated for 5 minutes. 55 μL (0.278 mmol) DIAD was added, the reaction mixture was sonicated for 5 minutes, then allowed to stand at room temperature for 17 hours. The solvent was evaporated under a stream of N₂ gas and the residue was redissolved in 2 mL DCM. The mixture was adsorbed on 0.43 g (1.3 mmol) macroporous polymer supported sulfonic acid and the resin was washed with 5 mL MeOH. The resin was eluted with 2×4 mL NH₃ (2 M in MeOH), the eluted mixtures were combined and concentrated. The residue was redissolved in 3 mL DCM and 1 mL TFA was added to the mixture. After evaporation, the product was purified by preparative HPLC (high-pH method). The purified product was dissolved in 3 mL DCM, 1 mL TFA was added and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated to give the desired product as a TFA salt.

Yield: 85 mg (53% of theory)

C₂₀H₂₂FN₅O (M=367.43)

predicted: Molecular ion (M+H)⁺: 368 observed: Molecular ion (M+H)⁺: 368

HPLC-MS: 1.62 minutes (Method B)

TABLE 8 Yield HPLC of final Mass retention step Salt spec time Example Structure (%) type result (method) 15.1 

64 TF 364 [M + H]⁺ 1.58 (B) 15.2 

99 TF 368 [M + H]⁺ 1.45 (B) 15.3 

99 TF 380 [M + H]⁺ 1.43 (B) 15.4 

99 TF 382 [M + H]⁺ 1.70 (B) 15.5 

57 TF 382 [M + H]⁺ 1.57 (B) 15.6 

99 TF 384/386 [M + H]⁺ 1.49 (B) 15.7 

99 TF 394 [M + H]⁺ 1.46 (B) 15.8 

99 TF 398 [M + H]⁺ 1.44 (B) 15.9 

56 TF 398 [M + H]⁺ 1.46 (B) 15.10

99 TF 400 [M + H]⁺ 1.62 (B) 15.11

99 TF 402/404 [M + H]⁺ 1.62 (B) 15.12

99 TF 402/404 [M + H]⁺ 1.63 (B) 15.13

55 TF 402/404 [M + H]⁺ 1.64 (B) 15.14

99 TF 402/404 [M + H]⁺ 1.52 (B) 15.15

99 TF 402/404 [M + H]⁺ 1.51 (B) 15.16

99 TF 414/416 [M + H]⁺ 1.53 (B) 15.17

41 TF 350 [M + H]⁺ 3.72 (C) 15.18

49 TF 364 [M + H]⁺ 4.03 (C) 15.19

40 TF 368 [M + H]⁺ 3.85 (C) 15.20

37 TF 380 [M + H]⁺ 3.74 (C) 15.21

18 TF 380 [M + H]⁺ 3.52 (C) 15.22

42 TF 394 [M + H]⁺ 3.99 (C) 15.23

37 TF 398 [M + H]⁺ 3.72 (C) 15.24

22 TF 400 [M + H]⁺ 4.11 (C) 15.25

21 TF 402/404 [M + H]⁺ 4.09 (C) 15.26

38 TF 414/416 [M + H]⁺ 3.94 (C) 15.27

 9 TF 414/416 [M + H]⁺ 3.92 (C) 15.28

52 none 351 [M + H]⁺ 4.20 (C)

Example 16 10-(3-Methoxymethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

16a 3-Methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester

To 24.6 mg (0.74 mmol, 60% dispersion in mineral oil) NaH in 5 mL THF at 0° C. was added 0.115 g (0.61 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared using route 15 step a) in 1 mL THF dropwise over 10 minutes, and the reaction was stirred at 0° C. for 30 minutes. 464 (0.74 mmol) methyl iodide was added and the reaction was stirred at room temperature for 2 hours. 20 mg (0.61 mmol, 60% dispersion in mineral oil) of NaH followed by 38 μL (0.61 mmol) of methyl iodide were added and the reaction mixture was stirred at room temperature for 16 hours. 5 mL of H₂O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO₄. After filtration, the solvent was evaporated to give the desired product which was used for the next step without further purification.

16b 3-Methoxymethyl-azetidine trifluoroacetate

To 0.123 g (0.61 mmol) 3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl in 2 mL DCM was added 0.47 mL (6.1 mmol) TFA and the reaction mixture was stirred for 16 hours. The solvent was evaporated to give the desired product as a TFA salt, which was used for the next step without further purification.

16d 10-(3-Methoxymethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared by using route 1 (step e and f), using 3-methoxymethyl-azetidine trifluoroacetate as the amine in step e (route 1).

Yield: 52.5 mg (60% of theory)

C₁₅H₂₁N₅O (M=287.37)

predicted: Molecular ion (M+H)⁺: 288 observed: Molecular ion (M+H)⁺: 288

HPLC-MS: 1.17 minutes (Method B)

TABLE 9 Yield of Mass HPLC final Salt spec retention time Example Structure step (%) type result (method) 16.1

93 HCl 274 [M + H]⁺ 1.17 (B)

Example 17 10-(3-Pyrazol-1-ylmethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

17a 3-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester

To 0.3 g (1.6 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (route 15, step a) in 3 mL DCM at 0° C. were added 0.33 mL (2.4 mmol) triethylamine and 0.19 mL (2.4 mmol) methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 3 hours. 10 mL DCM was added and the mixture was washed with H₂O (3×15 mL). The organic phase was dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 7:3 to 6:4).

Yield: 0.37 g (87% of theory)

C₁₀H₁₉NO₅S (M=265.33)

predicted: Molecular ion (M+H)⁺: 266 observed: Molecular ion (M+H)⁺: 266

HPLC-MS: 1.73 minutes (Method A)

17b 3-Pyrazol-1-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester

To 17.9 mg (0.26 mmol) pyrazole in 2 mL dry THF at 0° C. was added 14 mg (0.35 mmol, 60% dispersion in mineral oil) NaH and the reaction was stirred for 30 minutes. 50 mg (0.17 mmol) 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 1 mL dry THF was added dropwise and the reaction was allowed to warm to room temperature for 16 hours. The solvent was evaporated and the remaining residue was partitioned between 25 mL H₂O and 25 mL EtOAc. The organic phase was washed with 25 mL 1% citric acid solution, H₂O (3×25 mL), 25 mL brine and dried with Na₂SO₄. After filtration and evaporation of the solvent the product was used in the next step without further purification.

Yield: 41.5 mg (100% of theory)

C₁₂H₁₉N₃O₂ (M=237.30)

predicted: Molecular ion (M+H)⁺: 238 observed: Molecular ion (M+H)⁺: 238

HPLC-MS: 1.71 minutes (Method A)

17c 1-Azetidin-3-ylmethyl-1H-pyrazole

To 41.5 mg (0.17 mmol) 3-pyrazol-1-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL of 25% TFA in DCM and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.

17e 10-(3-Pyrazol-1-ylmethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 1-azetidin-3-ylmethyl-1H-pyrazole was used as the amine.

Yield: 23.3 mg (90% of theory)

C₁₇H₂₁N₇ (M=323.40)

predicted: Molecular ion (M+H)⁺: 324 observed: Molecular ion (M+H)⁺: 324

HPLC-MS: 4.28 minutes (Method C)

Example 18 10-(3-Pyridin-2-ylmethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

18a 3-Formyl-azetidine-1-carboxylic acid tert-butyl ester

To 40 mL dry DCM was added 2.19 mL (30.8 mmol) DMSO. The solution was cooled to −78° C. under nitrogen and 1.95 mL (23.1 mmol) oxalyl chloride was added dropwise. A solution of 2.88 g (15.4 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL dry DCM was added quickly via syringe followed by 10.5 mL (77 mmol) triethylamine. The mixture was allowed to warm to room temperature and then quenched by extraction with 1 M HCl (2×50 mL). The organic layer was dried over Na₂SO₄, filtered and evaporated to give the product which was used in the next step without further purification.

18b 3-(Hydroxy-pyridin-2-yl-methyl)-azetidine-1-carboxylic acid tert-butyl ester

To 1.51 g (9.55 mmol) bromopyridine in 50 mL ether at −20° C. was added 6 mL (1.6 M in hexane, 9.6 mmol) n-butyl lithium, after 10 minutes the mixture was cooled to −78° C. and 1.61 g (8.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL ether was added. The mixture was stirred and allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate solution and then extracted with 50 mL DCM. The organic layer was dried over Na₂SO₄. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 1:1 to EtOAc).

Yield: 0.5 g (22% of theory)

C₁₄H₂₀N₂O₃ (M=264.33)

predicted: Molecular ion (M+H)⁺: 265 observed: Molecular ion (M+H)⁺: 265

HPLC-MS: 0.93 minutes (Method D)

18c 3-(Methylsulfanylthiocarboxyoxy-pyridin-2-yl-methyl)-azetidine-1-carboxylic acid tert-butyl ester

To 529 mg (2 mmol) 3-(hydroxy-pyridin-2-yl-methyl)-azetidine-1-carboxylic acid tert-butyl ester in 10 mL dry THF was added 88 mg (2.2 mmol, 60% dispersion in mineral oil) NaH, and the mixture was stirred at room temperature for 10 minutes. 133 μL (2.4 mmol) carbon disulfide was added and the mixture was stirred for 30 minutes. 162 μL (2.6 mmol) methyl iodide was added and the mixture was stirred for 2 hours. 10 mL 1 M aqueous sodium bicarbonate was added and the mixture extracted with EtOAc (2×10 mL), the organic layers were combined and dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 9:1 to 7:3).

Yield: 737 mg (72% of theory)

C₁₆H₂₂N₂O₃S₂ (M=354.49)

predicted: Molecular ion (M+H)⁺: 355 observed: Molecular ion (M+H)⁺: 355

HPLC-MS: 1.52 minutes (Method D)

18d 3-Pyridin-2-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester

To 428 mg (1.21 mmol) 3-(methylsulfanylthiocarboxyoxy-pyridin-2-yl-methyl)-azetidine-1-carboxylic acid tert-butyl ester in 15 mL dry toluene was added 6 mg (36 μmol) AIBN followed by 508 mg (1.69 mmol) ^(n)Bu₃SnH, and the mixture was heated under nitrogen at 110° C. for 2 hours. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 1:1 to EtOAc).

Yield: 257 mg (86% of theory)

C₁₄H₂₀N₂O₂ (M=248.33)

predicted: Molecular ion (M+H)⁺: 249 observed: Molecular ion (M+H)⁺: 249

HPLC-MS: 0.91 minutes (Method D)

18e 2-Azetidin-3-ylmethyl-pyridine trifluoroacetate

To 257 mg (1.04 mmol) 3-pyridin-2-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL DCM and 2 mL TFA. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.

C₉H₁₂N₂ (M=148.21)

predicted: Molecular ion (M+H)⁺: 149 observed: Molecular ion (M+H)⁺: 149

HPLC-MS: 0.23 minutes (Method D)

18g 10-(3-Pyridin-2-ylmethyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-ylmethyl-pyridine trifluoroacetate was used as the amine.

Yield: 32 mg (4% of theory)

C₁₉H₂₂N₆ (M=334.43)

predicted: Molecular ion (M+H)⁺: 335 observed: Molecular ion (M+H)⁺: 335

HPLC-MS: 3.48 minutes (Method C)

TABLE 10 HPLC Yield of Mass retention final Salt spec time Example Structure step (%) type result (method) 18.1

63 TF 364 [M + H]⁺ 4.20 (C)

Example 19 (4-Methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanol

19a 3-[Hydroxy-(4-methoxy-phenyl)methyl]-azetidine-1-carboxylic acid tert-butyl ester

To 2.2 g (11.8 mmol) 4-bromoanisole in 30 mL dry heptane under nitrogen was added 8.02 mL (1.6 M in hexane, 12.83 mmol) n-butyl lithium dropwise, and the mixture was stirred at room temperature for 30 minutes. The solution was then cooled to −78° C. and a solution of 2.0 g (10.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (route 18, step a) in 30 mL dry THF was added. The resultant mixture was allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate and extracted with DCM (2×50 mL). The combined organic layers were dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 4:1 to 1:1).

Yield: 901 mg (29% of theory)

C₁₆H₂₃NO₄ (M=293.37)

predicted: Molecular ion (M+Na)⁺: 316 observed: Molecular ion (M+Na)⁺: 316

HPLC-MS: 1.30 minutes (Method D)

19b 3-(4-Methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester

To 30 mL dry DCM was added 0.45 mL (6.28 mmol) DMSO and the mixture was cooled to −78° C., 0.4 mL (4.71 mmol) oxalyl chloride was added followed by a solution of 920 mg (3.14 mmol) 3-[hydroxy-(4-methoxy-phenyl)methyl]-azetidine-1-carboxylic acid tert-butyl in 15 mL dry DCM. 2.14 mL (15.7 mmol) triethylamine was added, the mixture was allowed to warm to room temperature, washed with 1 M aqueous HCl (2×50 mL) and dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane-EtOAc 7:3 to 1:1).

Yield: 714 mg (78% of theory)

C₁₆H₂₁NO₄ (M=291.35)

predicted: Molecular ion (M+Na)⁺: 314 observed: Molecular ion (M+Na)⁺: 314

HPLC-MS: 1.30 minutes (Method D)

19c Azetidin-3-yl-(4-methoxy-phenyl)methanone trifluoroacetate

To 714 mg (2.45 mmol) 3-(4-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester in 10 mL DCM was added 10 mL TFA and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.

19e (4-Methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidin-3-yl-(4-methoxy-phenyl)methanone trifluoroacetate was used as the amine.

Yield: 912 mg (100% of theory)

C₂₁H₂₃N₅O₂ (M=377.45)

predicted: Molecular ion (M+H)⁺: 378 observed: Molecular ion (M+H)⁺: 378

HPLC-MS: 3.91 minutes (Method C)

19f (4-Methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanol

To 200 mg (0.53 mmol) (4-methoxy-phenyl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 3 mL MeOH was added 20 mg (0.53 mmol) sodium borohydride and the mixture was stirred at room temperature for 30 minutes. 1 mL saturated brine was added and the mixture extracted with DCM (2×5 mL), the organic layers were combined and dried over sodium sulphate. After filtration the solvent was evaporated to give the desired product.

Yield: 183 mg (91% of theory)

C₂₁H₂₅N₅O₂ (M=379.47)

predicted: Molecular ion (M+H)⁺: 380 observed: Molecular ion (M+H)⁺: 380

HPLC-MS: 3.54 minutes (Method C)

Example 20 10-(3-Benzyloxy-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

20a 10-(3-Hydroxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

The product was prepared using route 1 (step a to e), in step e (route 1) 3-hydroxyazetidine hydrochloride was used as the amine.

Yield: 212 mg (16% of theory)

C₁₈H₂₅N₅O₃ (M=359.43)

predicted: Molecular ion (M+H)⁺: 360 observed: Molecular ion (M+H)⁺: 360

HPLC-MS: 1.15 minutes (Method A)

20b 10-(3-Benzyloxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 200 mg (0.56 mmol) 10-(3-hydroxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF maintained at 0° C. for 30 minutes was added 320 mg (6.72 mmol, 60% dispersion in mineral oil) NaH under an atmosphere of nitrogen and the reaction was stirred at 0° C. for 30 minutes. 0.8 mL (6.80 mmol) benzyl bromide was added and the reaction was heated at 65° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated. 25 mL EtOAc was added and the organic layer was washed with H₂O (2×20 mL), and dried over Na₂SO₄. After filtration and evaporation the product was purified by column chromatography (silica, heptane/EtOAc 3:7).

Yield: 40 mg (16% of theory)

C₂₅H₃₁N₅O₃ (M=449.56)

predicted: Molecular ion (M+H)⁺: 450 observed: Molecular ion (M+H)⁺: 450

HPLC-MS: 1.67 minutes (Method A)

Rf: 0.30 (heptane/EtOAc 3:7)

20c 10-(3-Benzyloxy-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared by using route 1 (step e) using 10-(3-benzyloxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester as the boc-protected amine.

Yield: 21 mg (40% of theory)

C₂₀H₂₃N₅O (M=349.44)

predicted: Molecular ion (M+H)⁺: 350 observed: Molecular ion (M+H)⁺: 350

HPLC-MS: 3.83 minutes (Method C)

TABLE 11 HPLC Yield of Mass retention final Salt spec time Example Structure step (%) type result (method) 20.1 

 78 TF 316 [M + H]⁺ 3.85 (C) 20.2 

100 TF 288 [M + H]⁺ 2.74 (C) 20.3 

100 TF 314 [M + H]⁺ 3.23 (C) 20.4 

100 TF 356 [M + H]⁺ 4.72 (C) 20.5 

 11 TF 328 [M + H]⁺ 4.59 (C) 20.6 

 93 none 337 [M + H]⁺ 4.00 (C) 20.7 

100 TF 439/441 [M + H]⁺ 5.01 (C) 20.8 

 91 TF 405 [M + H]⁺ 4.73 (C) 20.9 

 95 none 405 [M + H]⁺ 4.73 (C) 20.10

 95 TF 405 [M + H]⁺ 4.65 (C) 20.11

 97 none 371/373 [M + H]⁺ 4.39 (C) 20.12

 81 none 405 [M + H]⁺ 4.55 (C) 20.13

 93 TF 380 [M + H]⁺ 4.13 (C) 20.14

 44 none 357 [M + H]⁺ 3.36 (C) 20.15

 87 TF 351 [M + H]⁺ 3.25 (C)

Example 21 10-(2-Phenyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

21a 2-Phenyl-azetidine

To 0.5 g (3.4 mmol) 4-phenyl-2-azetidinone in 5 mL anhydrous THF under nitrogen was added a solution of lithium aluminium hydride (1 M in THF, 11.9 mmol) dropwise, and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, 20% aqueous ammonium chloride was added and the mixture was filtered through a pad of celite. The filtrate was extracted with EtOAc (2×10 mL), the organic layers were combined and dried over Na₂SO₄. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/7 N ammonia in MeOH 92:2 to 94:6), which was used in the next step without further purification.

21c 10-(2-Phenyl-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-phenyl-azetidine was used as the amine.

Yield: 0.122 g (36% of theory)

C₁₉H₂₁N₅ (M=319.41)

predicted: Molecular ion (M+H)⁺: 320 observed: Molecular ion (M+H)⁺: 320

HPLC-MS: 3.24 minutes (Method C)

Example 22 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carbonitrile

22a Azetidine-3-carbonitrile hydrochloride

To 0.3 g (1.64 mmol) 1-N-boc-3-cyanoazetidine, was added 8.23 mL (32.9 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated to give the desired product as a HCl salt, which was used in the next step without further purification.

22c 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carbonitrile

The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidine-3-carbonitrile hydrochloride was used as the amine.

Yield: 0.2 g (87% of theory)

C₁₄H₁₆N (M=268.3)

predicted: Molecular ion (M+H)⁺: 269 observed: Molecular ion (M+H)⁺: 269

HPLC-MS: 3.12 minutes (Method C)

Example 23 10-Cyclobutyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

23a Cyclobutyl magnesium bromide

To 1.11 g (45.67 mmol) magnesium turnings in 5 mL THF was added 2 mg (7.9 μmol) iodine and the reaction was heated to 40° C. for 30 minutes. 0.5 g (3.7 mmol) cyclobutyl bromide was added and the reaction mixture was heated for 1.5 hours at 40° C. The mixture was cooled to room temperature and used in the next step.

23b 10-Cyclobutyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To a nitrogen purged mixture of 0.15 g (0.46 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 5 mL/0.5 mL THF/NMP in a sealed tube, was added 5.5 mg (0.022 mmol) iron (III) 2,4-pentanedionate. 0.5 mL (0.37 mmol) of cyclobutyl magnesium bromide in THF (23a) was added dropwise and the reaction was stirred at room temperature for 30 minutes. An extra 0.5 mL (0.37 mmol) of cyclobutyl magnesium bromide in THF (23a) was added and the reaction was stirred at room temperature for another 30 minutes. 5 mL EtOAc and 5 mL H₂O were added, and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO₄. After filtration and evaporation of the solvent the product was purified by preparative HPLC.

Yield: 0.021 g (13% of theory)

C₁₉H₂₆N₄O₂ (M=342.44)

predicted: Molecular ion (M+H)⁺: 343 observed: Molecular ion (M+H)⁺: 343

HPLC-MS: 2.17 minutes (Method A)

23c 10-Cyclobutyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using 10-cyclobutyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step f).

Yield: 14.4 mg (74% of theory)

C₁₄H₁₈N₄ (M=242.33)

predicted: Molecular ion (M+H)⁺: 243 observed: Molecular ion (M+H)⁺: 243

HPLC-MS: 1.47 minutes (Method B)

Example 24 10-(1,2,3,6-Tetrahydro-pyridin-4-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

24a 10-(1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

To 0.075 g (0.23 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in a microwave tube were added 3 mL dioxane, 1 mL MeOH, 79 mg (0.25 mmol) (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, 0.6 mL aqueous Na₂CO₃ (2 M), 19 mg (0.023 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) under nitrogen and the reaction was subjected to microwave irradiation (discoverer, 100° C., 250 Watts) for 15 minutes. After evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 100:2).

Yield: 33 mg (30% of theory)

C₂₅H₃₅N₅O₄ (M=469.59)

24b 10-(1,2,3,6-Tetrahydro-pyridin-4-yl)-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared by using route 1 (step f).

Yield: 12.9 mg (37% of theory)

C₁₅H₁₉N₅ (M=269.35)

predicted: Molecular ion (M+H)⁺: 270 observed: Molecular ion (M+H)⁺: 270

HPLC-MS: 1.11 minutes (Method B)

Example 25 3-Ethyl-10-piperidin-1-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

25e 3-Ethyl-10-piperidin-1-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using route 1 (step a to e), in step b (route 1) 4-ethyl-2H-pyrazol-3-ylamine (prepared according to J. Med. Chem. 1982, 25, 235-242) was used, in step e (route 1) piperidine was used as the amine.

Yield: 126 mg (84% of theory)

C₁₇H₂₅N₅ (M=299.42)

predicted: Molecular ion (M+H)⁺: 300 observed: Molecular ion (M+H)⁺: 300

HPLC-MS: 4.61 minutes (Method C)

TABLE 12 HPLC Yield of Mass retention final Salt spec time Example Structure step (%) type result (method) 25.1

63 TF 394 [M + H]⁺ 4.73 (C) 25.2

51 TF 272 [M + H]⁺ 3.74 (C)

Example 26 1-(3-Ethyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

26b 1-(3-Ethyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

The product was prepared using route 25 (step a to e), in step d (route 25) azetidine-3-carboxylic acid dimethylamide (route 9, step a and b) was used as the amine.

Yield: 161 mg (99% of theory)

C₁₈H₂₆N₆O (M=342.45)

predicted: Molecular ion (M+H)⁺: 343 observed: Molecular ion (M+H)⁺: 343

HPLC-MS: 3.51 minutes (Method C)

Example 27 10-Azetidin-1-yl-3-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

27e 10-Azetidin-1-yl-3-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using route 1 (from step a to f), in step b (route 1) 4-methyl-2H-pyrazol-3-ylamine was used, in step e (route 1) azetidine was used as the amine.

C₁₄H₁₉N₅ (M=257.34)

predicted: Molecular ion (M+H)⁺: 258 observed: Molecular ion (M+H)⁺: 258

HPLC-MS: 3.52 minutes (Method C)

TABLE 13 HPLC Yield of Mass retention final Salt spec time Example Structure step (%) type result (method) 27.1

46 TF 286 [M + H]⁺ 4.30 (C) 27.2

68 TF 380 [M + H]⁺ 4.44 (C)

Example 28 1-(3-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

28b 1-(3-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid dimethylamide

The product was prepared using route 27 (step a to e), in step d (route 27) azetidine-3-carboxylic acid dimethylamide (route 9, step a and b) was used as the amine.

C17H24N6O (M=328.42)

predicted: Molecular ion (M+H)⁺: 329 observed: Molecular ion (M+H)⁺: 329

HPLC-MS: 3.22 minutes (Method C)

Example 29 10-Azetidin-1-yl-3-cyclopropyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

29a 4-Cyclopropyl-2H-pyrazol-3-ylamine

To 7 g (0.3 mol) of freshly cut sodium chunks in 220 mL dry ether under nitrogen and external ice cooling was added a solution of 25 mL (0.3 mol) ethyl formate followed by a solution of 25 g (0.3 mol) cyclopropylacetonitrile in 50 mL dry ether, and the mixture was stirred at room temperature for 2 days. 19 mL (0.3 mol) glacial acetic acid was added whilst maintaining the internal temperature at 10-12° C., the solids were filtered off and the filtrate was concentrated at below 20° C. The residue was treated with 300 mL (0.6 mol) 2 M hydrazine in THF, 5 mL glacial acetic acid and heated at reflux for 2 hours. After cooling, the mixture was concentrated and the desired product was obtained by kugelrohr distillation. The product was used in the next step without further purification.

Yield: 6.9 g (18% of theory)

C₆H₉N₃ (M=123.16)

29f 10-Azetidin-1-yl-3-cyclopropyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

The product was prepared using route 1 (step b to f), in step b (route 1) 4-cyclopropyl-2H-pyrazol-3-ylamine was used, in step e (route 1) azetidine was used as the amine.

Yield: 81 mg (57% of theory)

C₁₆H₂₁N₅ (M=283.38)

predicted: Molecular ion (M+H)⁺: 284 observed: Molecular ion (M+H)⁺: 284

HPLC-MS: 3.81 minutes (Method C)

Example 30 7-Methyl-10-piperazin-1-yl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

0.2 g (0.62 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester were suspended in 5 mL acetonitrile. 0.23 mL HCl in dioxane (4 mol/l) were added and the reaction mixture was stirred at 60° C. over night. The solvents were removed to yield the desired product as a hydrochloride. Yield: 0.19 g (115% of theory). Subsequently 0.18 g of the intermediate, 59 μL formaldehyde (0.76 mmol) and 40 μL glacial acetic acid (0.7 mmol) were suspended in 20 mL THF. The reaction mixture was stirred at room temperature for 3 h. 0.34 g sodium cyanoborohydride (1.5 mmol) was added in portions and the mixture was stirred again at room temperature for 3 h. 20 mL aqueous potassium carbonate (15%) were added and the reaction was extracted with EtOAc. The organic layers were dried (Na₂SO₄), filtered, and the solvent was evaporated. The intermediate was purified by reversed phase prep. HPLC. Yield: 30 mg (18% of theory).

Subsequently the intermediate and 47 mg (0.25 mmol) piperazine-1-carboxylic acid tert-butyl ester were suspended in 2 mL NMP. The reaction mixture was stirred at 130° C. over night. The intermediate was purified by prep. HPLC and column chromatography (silica, EtOAc/MeOH/NH₄OH 9/1/0.1). Yield: 10.6 mg (36% of theory).

7 mg of the intermediate were suspended in 2 mL aqueous HCl (2 mol/l) and stirred at room temperature for 3 h. The reaction mixture was freeze-dried to yield the desired product as a hydrochloride.

Yield: 5.2 mg (80% of theory)

C₁₅H₂₂N₆×2HCl: 359.3

predicted: Molecular ion (M+H)⁺: 287 observed: Molecular ion (M+H)⁺: 287

Example 31 31a 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

10 g (31 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester were suspended in 750 mL ethanol. 13.2 g sodium hydrogencarbonate (155 mmol) and 3.6 g (36 mmol) azetidine-3-carboxylic acid were added and the reaction mixture was stirred at 70° C. for 36 h. After cooling down, the solvent was evaporated to 25 mL. The residue was washed several times with diethyl ether and the solvent was decanted. Then the residue was mixed again with 400 mL diethyl ether and the solid was filtered to yield the final product as a sodium salt.

Yield: 11.85 g (93% of theory)

C₁₉H₂₅N₅O₄: 387.4

predicted: Molecular ion (M+H)⁺: 388 observed: Molecular ion (M+H)⁺: 388

The 3-bromo and the 3-methyl derivatives were prepared following the same route using either 3-bromo-10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 2 step a-c) or 3-methyl-10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 27 step a-c) as starting materials.

31b (General Route)

10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (1 eq) was suspended in 1 mL DMF. DIPEA (1.5 eq) and TBTU (1.1 eq) were added and the reaction mixture was stirred for 30 min. The amine (1 eq) was added and the reaction was stirred at room temperature till no further conversion was observed. The intermediate was purified by prep. HPLC and the fractions were freeze-dried. The residue was suspended in 1 mL DCM/TFA 1/1 and stirred for 2 h. The solvent was evaporated to yield the final product. Products with a purity lower than 90%, were purified again by prep. HPLC.

The 3-bromo and the 3-methyl derivatives were prepared following the same route using 3-bromo-10-(3-carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester or, respectively, 3-methyl-10-(3-carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester as starting materials.

TABLE 14 Yield of final Salt Mass spec HPLC retention Example Structure step % type result time (method) 31.1 

81 TF 369.3 [M + H]⁺ 1.38 (F) 31.2 

59 TF 416.2 [M + H]⁺ 1.38 (F) 31.3 

38 TF 359.5 [M + H]⁺ 1.4 (J) 31.4 

21 TF 329.4 [M + H]⁺ 1.42 (J) 31.5 

13 TF 377.5 [M + H]⁺ 1.65 (J) 31.6 

9 TF 343.2 [M + H]⁺ 1.52 (J) 31.7 

26 TF 327.29 [M + H]⁺ 1.35 (J) 31.8 

39 TF 433.3 [M + H]⁺ 1.74 (J) 31.9 

39 TF 367.36 [M + H]⁺ 1.63 (J) 31.10 

26 TF 341.28 [M + H]⁺ 1.48 (J) 31.11 

26 TF 357.29 [M + H]⁺ 1.61 (J) 31.12 

31 TF 369.35 [M + H]⁺ 1.65 (J) 31.13 

27 TF 398.32 [M + H]⁺ 1.46 (J) 31.14 

49 TF 367.36 [M + H]⁺ 1.58 (J) 31.15 

55 TF 355.35 [M + H]⁺ 1.54 (J) 31.16 

40 TF 363.33 [M + H]⁺ 1.65 (J) 31.17 

35 TF 357.3 [M + H]⁺ 1.35 (J) 31.18 

37 TF 355.36 [M + H]⁺ 1.57 (J) 31.19 

38 TF 391.36 [M + H]⁺ 1.7 (J) 31.20 

11 TF 343.34 [M + H]⁺ 1.52 (J) 31.21 

46 TF 391.37 [M + H]⁺ 1.69 (J) 31.22 

87 TF 383.3 [M + H]⁺ 1.45 (F) 31.23 

75 TF 405.3 [M + H]⁺ 1.46 (F) 31.24 

40 TF 411.2 [M + H]⁺ 1.44 (F) 31.25 

95 TF 423.3 [M + H]⁺ 1.49 (F) 31.26 

88 TF 421.2 [M + H]⁺ 1.4 (F) 31.27 

88 TF 435.3 [M + H]⁺ 1.41 (F) 31.28 

98 TF 403.2 [M + H]⁺ 1.44 (F) 31.29 

134 TF 392.2 [M + H]⁺ 1.07 (F) 31.30 

98 TF 383.3 [M + H]⁺ 1.41 (F) 31.31 

90 TF 407.2 [M + H]⁺ 1.38 (F) 31.32 

80 TF 403.2 [M + H]⁺ 1.43 (F) 31.33 

70 TF 417.2 [M + H]⁺ 1.45 (F) 31.34 

107 TF 371.2 [M + H]⁺ 1.21 (F) 31.35 

101 TF 423.3 [M + H]⁺ 1.55 (F) 31.36 

89 TF 409.2 [M + H]⁺ 1.42 (F) 31.37 

72 TF 425.2 [M + H]⁺ 1.47 (F) 31.38 

25 TF 407.2 [M + H]⁺ 1.4 (F) 31.39 

90 TF 425.2 [M + H]⁺ 1.48 (F) 31.40 

76 TF 425.2 [M + H]⁺ 1.49 (F) 31.41 

93 TF 409.3 [M + H]⁺ 1.51 (F) 31.42 

104 TF 385.2 [M + H]⁺ 1.27 (F) 31.43 

16 TF 397.2 [M + H]⁺ 1.38 (F) 31.44 

76 TF 389.2 [M + H]⁺ 1.39 (F) 31.45 

90 TF 417.3 [M + H]⁺ 1.43 (F) 31.46 

31 TF 417.3 [M + H]⁺ 1.48 (F) 31.47 

28 TF 383.3 [M + H]⁺ 1.44 (F) 31.48 

90 TF 409.3 [M + H]⁺ 1.49 (F) 31.49 

91 TF 405.3 [M + H]⁺ 1.47 (F) 31.50 

95 TF 405.3 [M + H]⁺ 1.47 (F) 31.51 

89 TF 421.2 [M + H]⁺ 1.44 (F) 31.52 

115 TF 424.2 [M + H]⁺ 1.28 (F) 31.53 

80 TF 369 [M + H]⁺ 1.41 (K) 31.54 

122 TF 395.2 [M + H]⁺ 1.23 (F) 31.55 

20 TF 407.2 [M + H]⁺ 1.41 (F) 31.56 

72 BS 381 [M + H]⁺ 1.09 (M) 31.57 

96 TF 411.3 [M + H]⁺ 1.26 (F) 31.58 

123 TF 410.3 [M + H]⁺ 1.29 (F) 31.59 

65 TF 439.2 [M + H]⁺ 1.49 (F) 31.60 

49 TF 403.2 [M + H]⁺ 1.43 (F) 31.61 

45 TF 405.3 [M + H]⁺ 1.43 (F) 31.62 

70 TF 369.3 [M + H]⁺ 1.36 (F) 31.63 

91 TF 431.3 [M + H]⁺ 1.51 (F) 31.64 

75 TF 341.2 [M + H]⁺ 1.22 (F) 31.65 

63 TF 451.3 [M + H]⁺ 1.54 (F) 31.66 

38 TF 343.2 [M + H]⁺ 1.28 (F) 31.67 

48 BS 423 [M + H]⁺ 0.75 (P) 31.68 

30 TF 383.2 [M + H]⁺ 1.57 (F) 31.69 

31 TF 397.3 [M + H]⁺ 1.64 (F) 31.70 

24 TF 437.2 [M + H]⁺ 1.76 (F) 31.71 

22 TF 455.2 [M + H]⁺ 1.64 (F) 31.72 

26 TF 507.2 [M + H]⁺ 1.75 (F) 31.73 

22 TF 355.2 [M + H]⁺ 1.45 (F) 31.74 

23 TF 371.2 [M + H]⁺ 1.54 (F) 31.75 

35 TF 405.2 [M + H]⁺ 1.62 (F) 31.76 

30 TF 441.2 [M + H]⁺ 1.63 (F) 31.77 

17 TF 467.2 [M + H]⁺ 1.71 (F) 31.78 

25 TF 470 [M + H]⁺ 1.67 (F) 31.79 

15 TF 471.1 [M + H]⁺ 1.61 (F) 31.80 

22 TF 471.1 [M + H]⁺ 1.62 (F) 31.81 

18 TF 459.1 [M + H]⁺ 1.74 (F) 31.82 

30 TF 467.2 [M + H]⁺ 1.72 (F) 31.83 

24 TF 423.2 [M + H]⁺ 1.35 (F) 31.84 

21 TF 411.3 [M + H]⁺ 1.76 (F) 31.85 

30 TF 397.2 [M + H]⁺ 1.61 (F) 31.86 

23 TF 467.2 [M + H]⁺ 1.77 (F) 31.87 

29 TF 459.2 [M + H]⁺ 1.72 (F) 31.88 

28 TF 443.2 [M + H]⁺ 1.66 (F) 31.89 

19 TF 473.2 [M + H]⁺ 1.65 (F) 31.90 

30 TF 405.2 [M + H]⁺ 1.56 (F) 31.91 

27 TF 405.2 [M + H]⁺ 1.56 (F) 31.92 

28 TF 403.2 [M + H]⁺ 1.51 (F) 31.93 

34 TF 421.2 [M + H]⁺ 1.61 (F) 31.94 

19 TF 301.1 [M + H]⁺ 1.66 (F) 31.95 

21 TF 409.2 [M + H]⁺ 1.51 (F) 31.96 

27 TF 409.2 [M + H]⁺ 1.54 (F) 31.97 

28 TF 355.2 [M + H]⁺ 1.42 (F) 31.98 

26 TF 417.2 [M + H]⁺ 1.57 (F) 31.99 

27 TF 445.2 [M + H]⁺ 1.67 (F) 31.100

23 TF 397.2 [M + H]⁺ 1.62 (F) 31.101

30 TF 463.2 [M + H]⁺ 1.67 (F) 31.102

28 TF 471.2 [M + H]⁺ 1.66 (F) 31.103

18 TF 419.2 [M + H]⁺ 1.61 (F) 31.104

24 TF 395.2 [M + H]⁺ 1.59 (F) 31.105

26 TF 477.2 [M + H]⁺ 1.75 (F) 31.106

13 TF 395.2 [M + H]⁺ 1.57 (F) 31.107

25 TF 471.2 [M + H]⁺ 1.68 (F) 31.108

29 TF 431.2 [M + H]⁺ 1.63 (F) 31.109

25 TF 499.1 [M + H]⁺ 1.74 (F) 31.110

28 TF 449.2 [M + H]⁺ 1.65 (F) 31.111

28 TF 465.2 [M + H]⁺ 1.69 (F) 31.112

18 TF 511.1 [M + H]⁺ 1.73 (F) 31.113

29 TF 449.2 [M + H]⁺ 1.63 (F) 31.114

24 TF 467.1 [M + H]⁺ 1.68 (F) 31.115

29 TF 465.2 [M + H]⁺ 1.7 (F) 31.116

32 TF 435.2 [M + H]⁺ 1.58 (F) 31.117

32 TF 449.2 [M + H]⁺ 1.63 (F) 31.118

30 TF 435.2 [M + H]⁺ 1.59 (F) 31.119

28 TF 417.2 [M + H]⁺ 1.55 (F) 31.120

23 TF 465.2 [M + H]⁺ 1.77 (F) 31.121

26 TF 411.3 [M + H]⁺ 1.8 (F) 31.122

30 TF 471.1 [M + H]⁺ 1.64 (F) 31.123

32 TF 395.2 [M + H]⁺ 1.55 (F) 31.124

38 TF 355.2 [M + H]⁺ 1.4 (F) 31.125

28 TF 409.2 [M + H]⁺ 1.54 (F) 31.126

35 TF 445.2 [M + H]⁺ 1.68 (F) 31.127

28 TF 409.2 [M + H]⁺ 1.6 (F) 31.128

24 TF 431.2 [M + H]⁺ 1.63 (F) 31.129

19 TF 433.2 [M + H]⁺ 1.6 (F) 31.130

34 TF 409.2 [M + H]⁺ 1.63 (F) 31.131

24 TF 409.2 [M + H]⁺ 1.61 (F) 31.132

15 TF 501/503 [M + H]⁺ 1.75 (G) 31.133

21 TF 459/461 [M + H]⁺ 1.55 (G) 31.134

24 TF 487/489 [M + H]⁺ 1.51 (G) 31.135

28 TF 447/449 [M + H]⁺ 1.51 (G) 31.136

28 TF 481/483 [M + H]⁺ 1.59 (G) 31.137

24 TF 489/491 [M + H]⁺ 1.41 (G) 31.138

19 TF 461/463 [M + H]⁺ 1.6 (G) 31.139

15 TF 494/496 [M + H]⁺ 1.53 (G) 31.140

16 TF 463/465 [M + H]⁺ 1.43 (G) 31.141

19 TF 503/505/507 [M + H]⁺ 1.65 (G) 31.142

18 TF 369.1 [M + H]⁺ 1.31 (F) 31.143

21 TF 389.1 [M + H]⁺ 1.38 (F) 31.144

15 TF 445.2 [M + H]⁺ 1.53 (F) 31.145

17 TF 481.1 [M + H]⁺ 1.52 (F) 31.146

16 TF 483.2 [M + H]⁺ 1.53 (F) 31.147

17 TF 423.1 [M + H]⁺ 1.48 (F) 31.148

18 TF 377.1 [M + H]⁺ 1.25 (F) 31.149

18 TF 459.1 [M + H]⁺ 1.49 (F) 31.150

19 TF 480.2 [M + H]⁺ 1.38 (F) 31.151

21 TF 438.2 [M + H]⁺ 1.19 (F) 31.152

20 TF 445.2 [M + H]⁺ 1.5 (F) 31.153

17 TF 459.2 [M + H]⁺ 1.43 (F) 31.154

20 TF 447.2 [M + H]⁺ 1.48 (F) 31.155

19 TF 425.1 [M + H]⁺ 1.46 (F) 31.156

26 TF 403.1 [M + H]⁺ 1.46 (F) 31.157

10 TF 457.1 [M + H]⁺ 1.52 (F) 31.158

22 TF 409.2 [M + H]⁺ 1.43 (F) 31.159

12 TF 366.1 [M + H]⁺ 1.14 (F) 31.160

17 TF 459.1 [M + H]⁺ 1.46 (F) 31.161

18 TF 457.1 [M + H]⁺ 1.45 (F) 31.162

20 TF 447.2 [M + H]⁺ 1.57 (F) 31.163

17 TF 433.2 [M + H]⁺ 1.53 (F) 31.164

14 TF 459.1 [M + H]⁺ 1.51 (F) 31.165

11 TF 459.1 [M + H]⁺ 1.52 (F) 31.166

22 TF 381.2 [M + H]⁺ 1.35 (F) 31.167

20 TF 445.2 [M + H]⁺ 1.52 (F) 31.168

14 TF 459.1 [M + H]⁺ 1.5 (F) 31.169

18 TF 441.2 [M + H]⁺ 1.49 (F) 31.170

22 TF 419.2 [M + H]⁺ 1.49 (F) 31.171

10 TF 431.2 [M + H]⁺ 1.47 (F) 31.172

18 TF 471.3 [M + H]⁺ 1.55 (F) 31.173

20 TF 457.2 [M + H]⁺ 1.52 (F) 31.174

15 TF 403.2 [M + H]⁺ 1.43 (F) 31.175

20 TF 403.2 [M + H]⁺ 1.44 (F) 31.176

18 TF 403.2 [M + H]⁺ 1.45 (F) 31.177

16 TF 431.2 [M + H]⁺ 1.47 (F) 31.178

98 TF 353.3 [M + H]⁺ 1.26 (G) 31.179

57 TF 383.4 [M + H]⁺ 1.48 (G) 31.180

40 TF 383.4 [M + H]⁺ 1.49 (G) 31.181

37 TF 429.4 [M + H]⁺ 1.54 (G) 31.182

21 TF 432.6 [M + H]⁺ 1.15 (G) 31.183

77 TF 339.2 [M + H]⁺ 1.23 (G) 31.184

54 TF 397.4 [M + H]⁺ 1.51 (G) 31.185

36 TF 489.5 [M + H]⁺ 1.64 (G) 31.186

58 TF 461.4 [M + H]⁺ 1.54 (G) 31.187

8 TF 432.6 [M + H]⁺ 1.19 (G) 31.188

33 TF 397.4 [M + H]⁺ 1.54 (G) 31.189

77 TF 397.4 [M + H]⁺ 1.53 (G) 31.190

3 TF 417.4 [M + H]⁺ 1.53 (G) 31.191

38 TF 130.3 [M + H]⁺ 1.14 (G) 31.192

21 TF 367.3 [M + H]⁺ 1.37 (G) 31.193

78 TF 373.3 [M + H]⁺ 1.29 (G) 31.194

13 TF 399.4 [M + H]⁺ 1.3 (G) 31.195

36 TF 483.5 [M + H]⁺ 1.41 (G) 31.196

69 TF 406.6 [M + H]⁺ 1.13 (G) 31.197

45 TF 485.5 [M + H]⁺ 1.64 (G) 31.198

34 TF 451.5 [M + H]⁺ 1.61 (G) 31.199

27 TF 461.5 [M + H]⁺ 1.54 (G) 31.200

56 TF 413.3 [M + H]⁺ 1.43 (G) 31.201

46 TF 391.5 [M + H]⁺ 1.35 (G) 31.202

76 TF 359.5 [M + H]⁺ 1.23 (G) 31.203

57 TF 391.3 [M + H]⁺ 1.36 (G) 31.204

53 TF 421.4 [M + H]⁺ 1.49 (G) 31.205

95 TF 359.5 [M + H]⁺ 1.22 (G) 31.206

68 TF 373.4 [M + H]⁺ 1.3 (G) 31.207

16 TF 483.3 [M + H]⁺ 1.56 (G) 31.208

73 TF 406.5 [M + H]⁺ 1.12 (G) 31.209

31 TF 483.4 [M + H]⁺ 1.57 (G) 31.210

5 BS 446.6 [M + H]⁺ 1.25 (G) 31.211

50 TF 449.4 [M + H]⁺ 1.58 (G) 31.212

30 TF 433.4 [M + H]⁺ 1.49 (G) 31.213

42 TF 467.4 [M + H]⁺ 1.57 (G) 31.214

31 TF 499.4 [M + H]⁺ 1.71 (G) 31.215

48 TF 449.4 [M + H]⁺ 1.57 (G) 31.216

40 TF 411.4 [M + H]⁺ 1.61 (G) 31.217

59 TF 407.4 [M + H]⁺ 1.49 (G) 31.218

44 TF 419.4 [M + H]⁺ 1.47 (G) 31.219

49 TF 489.5 [M + H]⁺ 1.71 (G) 31.220

90 TF 399.4 [M + H]⁺ 1.34 (G) 31.221

60 TF 507.5 [M + H]⁺ 1.66 (G) 31.222

58 TF 457.5 [M + H]⁺ 1.6 (G) 31.223

65 TF 417.4 [M + H]⁺ 1.5 (G) 31.224

46 TF 417.4 [M + H]⁺ 1.5 (G) 31.225

59 TF 383.4 [M + H]⁺ 1.5 (G) 31.226

38 TF 515.5 [M + H]⁺ 1.55 (G) 31.227

36 TF 515.5 [M + H]⁺ 1.57 (G) 31.228

36 TF 369.3 [M + H]⁺ 1.42 (G) 31.229

45 TF 367.3 [M + H]⁺ 1.4 (G) 31.230

51 TF 448.6 [M + H]⁺ 1.32 (G) 31.231

15 TF 435.4 [M + H]⁺ 1.5 (G) 31.232

43 TF 443.5 [M + H]⁺ 1.56 (G) 31.233

22 TF 443.4 [M + H]⁺ 1.56 (G) 31.234

60 BS 403 [M + H]⁺ 1.17 (M) 31.235

58 TF 437.5 [M + H]⁺ 1.64 (F) 31.236

47 TF 403.2 [M + H]⁺ 1.51 (F) 31.237

43 TF 437.2 [M + H]⁺ 1.5 (F) 31.238

31 TF 405.2 [M + H]⁺ 1.41 (F) 31.239

32 TF 485.2 [M + H]⁺ 1.62 (F) 31.240

31 TF 425.2 [M + H]⁺ 1.34 (F) 31.241

35 TF 417.2 [M + H]⁺ 1.55 (F) 31.242

19 TF 473.2 [M + H]⁺ 1.54 (F) 31.243

42 TF 463.2 [M + H]⁺ 1.6 (F) 31.244

43 TF 461.2 [M + H]⁺ 1.58 (F) 31.245

56 TF 421.2 [M + H]⁺ 1.53 (F) 31.246

46 TF 471.4 [M + H]⁺ 1.63 (F) 31.247

54 TF 433.2 [M + H]⁺ 1.5 (F) 31.248

64 TF 409.2 [M + H]⁺ 1.52 (F) 31.249

17 TF 471.2 [M + H]⁺ 1.56 (F) 31.250

38 TF 430.2 [M + H]⁺ 1.46 (F)

Example 32 32a 10-(3-Carboxy-3-methyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

3.5 g (10.8 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, 2 g (12 mmol) 3-methyl-azetidine-3-carboxylic acid methyl ester hydrochloride and 6 mL (3.9 eq) triethyl amine were suspended in 100 mL NMP. The reaction mixture was stirred at 120° C. over night. After cooling down, the solvent was evaporated and the residue was purified by prep. HPLC to yield the corresponding ester as an intermediate (18% of theory).

0.82 g (1.96 mmol) of the ester intermediate were subsequently dissolved in 10 mL THF and 15 mL water and were treated with 82 mg (1.96 mmol) LiOH. The reaction mixture was stirred at room temperature for 2 h. The solvents were removed by distillation and lyophylisation to yield the lithium salt quantitative yield (0.83 g)

C₂₀H₂₆N₅O₄*Li: 407.4

predicted: Molecular ion (M+H)⁺: 402 (protonated acid) observed: Molecular ion (M+H)⁺: 402

32b (General Route)

10-(3-Carboxy-3-methyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (1 eq) was suspended in 1 mL DMF. DIPEA (1.5 eq) and TBTU (1.1 eq) were added and the reaction mixture was stirred for 30 min. The amine (1 eq) was added and the reaction was stirred at room temperature till no further conversion was observed. The intermediate was purified by prep. HPLC and the fractions were freeze-dried. The residue was suspended in 1 mL DCM/TFA 1/1 and stirred for 2 h. The solvent was evaporated to yield the final product. Products with a purity lower than 90%, were purified again by prep. HPLC.

TABLE 15 Yield of HPLC final retention step Salt Mass spec time Example Structure (%) type result (method) 32.1

 2 TF 460.2 [M + H]⁺ 1.63 (F) 32.2

10 TF 437.2 [M + H]⁺ 1.49 (F) 32.3

10 TF 485.2 [M + H]⁺ 1.62 (F) 32.4

 2 TF 425.2 [M + H]⁺ 1.32 (F) 32.5

10 TF 473.2 [M + H]⁺ 1.54 (F) 32.6

10 TF 463.2 [M + H]⁺ 1.59 (F) 32.7

 4 TF 460.2 [M + H]⁺ 1.57 (F) 32.8

11 TF 409.2 [M + H]⁺ 1.53 (F)

Example 33 33a 10-(3-Carboxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

2.5 g (7.75 mmol) 10-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, 1.1 g (9.1 mmol) azetidin-3-yl-acetic acid and 3 mL (17.4 mmol) DIPEA were suspended in 18 mL ethanol. The reaction mixture was stirred at 75° C. over night. The solvent was evaporated and the residue was taken up in EtOAc and water and was acidified using a KHSO₄ solution. The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by prep. HPLC to yield the corresponding acid (72% of theory).

C₂₀H₂₆N₅O₄: 401.5

predicted: Molecular ion (M+H)⁺: 402 observed: Molecular ion (M+H)⁺: 402

33b (General Route)

10-(3-Carboxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (1 eq) was suspended in 1 mL DMF. DIPEA (1.5 eq) and TBTU (1.1 eq) were added and the reaction mixture was stirred for 30 min. The amine (1 eq) was added and the reaction was stirred at room temperature till no further conversion was observed. The intermediate was purified by prep. HPLC and the fractions were freeze-dried. The residue was suspended in 1 mL DCM/TFA 1/1 and stirred for 2 h. The solvent was evaporated to yield the final product. Products with a purity lower than 90%, were purified again by prep. HPLC.

TABLE 16 Yield of final Salt Mass spec HPLC retention Example Structure step % type result time (method) 33.1

21 TF 403.2 [M + H]⁺  1.5 (F) 33.2

21 TF 421.2 [M + H]⁺ 1.52 (F) 33.3

 1 TF 433.2 [M + H]⁺ 1.48 (F)

Example 34 General Route

-   10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic     acid tert-butyl ester (1 eq), TBTU (1.1 eq) and DIPEA (1.5 eq) were     suspended in DMF. This mixture was added to the corresponding     diamine at room temperature.

In case the phenylen diamine was not available, the corresponding 2-nitro-aminoaryl derivative was used and its nitro group was reduced to the free amine prior to reacting it with the acid in order to form the amide. The reduction of the nitro group was conducted in MeOH/THF (1/1) together with 10 mol % Pd/C and hydrochloric acid under a hydrogen atmosphere at 3 bar for 5 h.

Subsequently the reaction mixture (diamine and acid) was stirred until no further conversion could be observed. Purification using prep. HPLC yielded the corresponding amide as an intermediate. The intermediate was then taken up in glacial acetic acid and was stirred at elevated temperature 80-120° C. until no further conversion was observed. After removal of the solvent the residue was treated with DCM/TFA 1/1 (containing 5% H₂O) and stirred for 1 h at room temperature. After purification using prep. HPLC one could obtain the desired product.

TABLE 17 overall HPLC yield Salt Mass spec retention time Example Structure (%) type result (method) 34

65 TF 360   [M + H]⁺ 1.48 (J) 34.1

65 TF 374   [M + H]⁺ 1.46 (J) 34.2

21 TF 388.1 [M + H]⁺ 1.22 (H) 34.3

17 TF 409   [M + H]⁺ 1.32 (H) 34.4

15 TF 392.1 [M + H]⁺ 1.24 (H) 34.5

6 BS 374.1 [M + H]⁺ 1.23 (H) 34.6

19 TF 409   [M + H]⁺ 1.33 (H) 34.7

31 TF 456.1 [M + H]⁺ 1.47 (H) 34.8

11 TF 457.1 [M + H]⁺ 1.5  (H) 34.9

20 TF 395   [M + H]⁺ 1.29 (H) 34.10

15 TF 428.2 [M + H]⁺ 1.39 (H) 34.11

20 TF 374.1 [M + H]⁺ 1.25 (H) 34.12

15 TF 388.1 [M + H]⁺ 1.3  (H) 34.13

8 TF 429.2 [M + H]⁺ 1.42 (H) 34.14

23 TF 378.2 [M + H]⁺ 1.22 (H) 34.15

14 TF 416.2 [M + H]⁺ 1.39 (H) 34.16

19 TF 470.6 [M + H]⁺ 1.52 (H) 34.17

30 TF 413   [M + H]⁺ 1.36 (H) 34.18

13 TF 399.1 [M + H]⁺ 1.3  (H) 34.19

9 TF 410.1 [M + H]⁺ 1.33 (H) 34.20

14 TF 442.2 [M + H]⁺ 1.39 (H) 34.21

24 TF 388.1 [M + H]⁺ 1.29 (H) 34.22

17 TF 454.1 [M + H]⁺ 1.35 (H) 34.23

40 TF 396.1 [M + H]⁺ 1.34 (H) 34.24

26 TF 396.1 [M + H]⁺ 1.34 (H) 34.25

11 TF 388.1 [M + H]⁺ 1.29 (H) 34.26

24 TF 416.2 [M + H]⁺ 1.34 (H) 34.27

32 TF 451.2 [M + H]⁺ 1.17 (H) 34.28

18 TF 450.2 [M + H]⁺ 1.38 (H) 34.29

20 TF 428.2 [M + H]⁺ 1.34 (H) 34.30

20 TF 408.1 [M + H]⁺ 1.34 (H) 34.31

9 TF 428.1 [M + H]⁺ 1.44 (H) 34.32

38 TF 471   [M + H]⁺ 1.51 (H) 34.33

27 TF 443   [M + H]⁺ 1.43 (H) 34.34

10 TF 518.2 [M + H]⁺ 1.59 (H) 34.35

53 TF 402.2 [M + H]⁺ 1.28 (H) 34.36

17 TF 464.2 [M + H]⁺ 1.38 (H) 34.37

6 TF 499.1 [M + H]⁺ 1.56 (H) 34.38

51 TF 392.5 [M + H]⁺ 1.41 (H) 34.39

51 TF 406.4 [M + H]⁺ 1.45 (H)

Example 35 10-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

27 mg (0.21 mmol) 4-Chlorophenole and 75 mg (0.23 mmol) Cs₂(CO)₃ were suspended in 1 mL DMA and the mixture was stirred for 30 min at room temperature. 50 mg (0.2 mmol) 3-Methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester in 1 mL DMA was added and stirring was continued over night at 80° C. The reaction mixture was filtered over basic aluminium oxide followed by washing with DMF/MeOH 9/1. The solvents were removed under reduced pressure and the residue dissolved in dichloromethane (1 mL) and was treated with 1.5 mL DCM/TFA 1/1. After 4 h the solvents were again removed. A mixture of 32 mg (0.1 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

in 1 mL EtOH and 0.053 mL (0.3 mmol) DIPEA was added and the reaction mixture was stirred at 80° C. over night. The solvent was removed and the residue was treated with 1 mL DCM/TFA 1/1 for 4 h followed by solvent removal. Finally the residue was purified by prep. HPLC to yield 10-[3-(4-chloro-phenoxy)-azetidin-1-yl]-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetra-aza-cyclohepta[f]indene as its TFA salt after lyophylisation (14 mg, 29% of theory)

Yield: 14 mg (29% of theory)

C₁₉H₂₀ClN₅O (M=369.86)

predicted: Molecular ion (M+H)⁺: 370 observed: Molecular ion (M+H)⁺: 370

HPLC-MS: 1.5 minutes (Method H)

TABLE 18 Overall HPLC yield Salt Mass spec retention time Example Structure (%) type result (method) 35.1

16 TF 417.1 [M + H]⁺ 1.33 (H) 35.2

24 TF 416   [M + H]⁺ 1.51 (H) 35.3

25 TF 370.1 [M + H]⁺ 1.46 (H) 35.4

16 TF 361.1 [M + H]⁺ 1.4  (H) 35.5

23 TF 350.2 [M + H]⁺ 1.48 (H) 35.6

5 TF 364.2 [M + H]⁺ 1.53 (H) 35.7

5 TF 416   [M + H]⁺ 1.48 (H) 35.8

1 TF 378.2 [M + H]⁺ 1.57 (H) 35.9

5 TF 378.2 [M + H]⁺ 1.57 (H) 35.10

6 TF 386.2 [M + H]⁺ 1.53 (H) 35.11

7 TF 416.2 [M + H]⁺ 1.57 (H) 35.12

3 TF 379.1 [M + H]⁺ 1.43 (H) 35.13

13 TF 416.2 [M + H]⁺ 1.54 (H) 35.14

27 TF 416   [M + H]⁺ 1.51 (H) 35.15

11 TF 389.1 [M + H]⁺ 1.47 (H) 35.16

6 TF 387.5 [M + H]⁺ 0.56 (H) 35.17

8 TF 446.1 [M + H]⁺ 1.49 (H) 35.18

7 TF 420.1 [M + H]⁺ 1.53 (H) 35.19

7 TF 400.1 [M + H]⁺ 1.48 (H) 35.20

11 TF 384.1 [M + H]⁺ 1.55 (H) 35.21

15 TF 400.1 [M + H]⁺ 1.48 (H) 35.22

13 TF 388.1 [M + H]⁺ 1.51 (H) 35.23

8 TF 365.5 [M + H]⁺ 0.56 (H) 35.24

14 TF 351.5 [M + H]⁺ 0.57 (H) 35.25

7 TF 390.2 [M + H]⁺ 1.58 (H) 35.26

5 TF 453.1 [M + H]⁺ 1.41 (H) 35.27

14 TF 380.2 [M + H]⁺ 1.48 (H) 35.28

27 TF 407.1 [M + H]⁺ 1.31 (H) 35.29

33 TF 384.1 [M + H]⁺ 1.52 (H) 35.30

25 TF 446.1 [M + H]⁺ 1.49 (H) 35.31

8 TF 404.1 [M + H]⁺ 1.51 (H) 35.32

16 TF 420.1 [M + H]⁺ 1.56 (H) 35.33

31 TF 400.1 [M + H]⁺ 1.45 (H) 35.34

25 TF 384.1 [M + H]⁺ 1.44 (H) 35.35

8 TF 371.1 [M + H]⁺ 1.24 (H) 35.36

7 TF 422.1 [M + H]⁺ 1.53 (H) 35.37

8 TF 380.1 [M + H]⁺ 1.44 (H) 35.38

1 TF 394.2 [M + H]⁺ 1.51 (H) 35.39

2 TF 402.1 [M + H]⁺ 1.49 (H) 35.40

1 TF 361.1 [M + H]⁺ 1.38 (H) 35.41

27 TF 372.1 [M + H]⁺ 1.42 (H) 35.42

23 TF 337.2 [M + H]⁺ 0.57 (H) 35.43

16 TF 387.5 [M + H]⁺ 1.17 (H) 35.44

18 TF 378.2 [M + H]⁺ 1.57 (H) 35.45

13 TF 350.2 [M + H]⁺ 1.47 (H) 35.46

5 TF 386.2 [M + H]⁺ 1.53 (H) 35.47

100 TF 366   [M + H]⁺ 4.37 (C) 35.48

78 TF 406   [M + H]⁺ 3.96 (C) 35.49

84 TF 396.1 [M + H]⁺ 1.4  (F) 35.50

95 TF 370.1 [M + H]⁺ 1.51 (F) 35.51

88 TF 350.1 [M + H]⁺ 1.49 (F) 35.52

58 TF 351.1 [M + H]⁺ 1.07 (F) 35.53

85 TF 380.1 [M + H]⁺ 1.48 (F) 35.54

95 TF 366.1 [M + H]⁺ 1.39 (F) 35.55

84 TF 372.1 [M + H]⁺ 1.48 (F)

Example 36 General Route (4-Ethyl-piperazin-1-yl)-[1-(7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone

36a 10-Chloro-7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene

To 20.0 g (77.2 mmol) 10-Chloro-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 200 mL buffer (pH=5) 6.4 mL formaldehyde (37% in water, 84.9 mmol) and 19.7 g sodium triacetoxyborohydride (93.0 mmol) were added under cooling with ice and stirring was continued over night. The mixture was then diluted at 0° C. with K₂CO₃-solution (15% in water) and extracted with ethyl acetate. The organic layers were combined, dried (Na₂SO₄) and concentrated. The residue was then purified by column chromatography (silica, EtOAc/MeOH/NH₄OH=9:1:0.1) to give the desired product.

Yield: 11.4 g (62% of theory)

C₁₁H₁₃ClN₄ (M=236.7)

predicted: Molecular ion (M+H)⁺: 237 observed: Molecular ion (M+H)⁺: 237

HPLC-MS: 1.4 minutes (Method K)

36b 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid

To 1.77 g (7.48 mmol) 10-Chloro-7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 50 mL ethanol was added 0.83 g (8.22 mmol) 3-azetidinecarboxylic acid and 2.75 mL (15.7 mmol) DIPEA and the reaction mixture was heated at 75° C. for 4 hours. The mixture was concentrated and treated with diethyl ether and methanol. After ultrasound irradiation, a precipitate formed which was collected by filtration. The remaining solution was concentrated and the above mentioned procedure was repeated. The precipitates were combined and dried to yield the desired product as the DIPEA-salt.

Yield: 3.29 g (100% of theory)

C₁₅H₁₉N₅O₂*C₈H₁₉N (M=430.59)

predicted: Molecular ion (M+H)⁺: 302 observed: Molecular ion (M+H)⁺: 302

HPLC-MS: 0.4 minutes (Method K)

36c 10(4-Ethyl-piperazin-1-yl)-[1-(7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone

To 11.4 mg (0.10 mmol) N-ethylpiperazine was added a solution of 43 mg (0.10 mmol) 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid and 0.026 mL (0.15 mmol) DIPEA in 0.5 mL DMF at room temperature. 35.3 mg (0.11 mmol) TBTU was dissolved in 0.5 mL DMF and the solution was added to the reaction mixture. Stirring was continued for 2 h and the reaction mixture was allowed to stand for overnight. The mixture was filtered over basic alumina followed by two washing cycles with 1.5 mL DMF. The solvent was removed and the residue was purified by column chromatography to yield the desired compound.

Yield: 3.7 mg (9.3% of theory)

C₂₁H₃₁N₇O (M=397.52)

predicted: Molecular ion (M+H)⁺: 398 observed: Molecular ion (M+H)⁺: 398

HPLC-MS: 0.7 minutes (Method Q)

In case that TF salts are listed a mixture of dichloromethane and TFA (1/1) was used to remove the boc-protection group

TABLE 19 Yield of final HPLC step Salt Mass spec retention time Example Structure (%) type result (method) 36.1

9.3 none 398.5 [M + H]⁺ 0.7 (R) 36.2

7.0 none 386.5 [M + H]⁺ 0.69 (R) 36.3

8.7 none 412.6 [M + H]⁺ 0.75 (R) 36.4

13.1 none 412.6 [M + H]⁺ 0.8  (R) 36.5

10.2 none 412.6 [M + H]⁺ 0.72 (R) 36.6

19.7 none 412.6 [M + H]⁺ 0.79 (R) 36.7

14.1 none 412.6 [M + H]⁺ 0.73 (R) 36.8

16.7 none 438.6 [M + H]⁺ 0.86 (R) 36.9

21.2 none 440.6 [M + H]⁺ 0.79 (R) 36.10

7.1 none 424.6 [M + H]⁺ 0.81 (R) 36.11

8.6 none 385.5 [M + H]⁺ 0.69 (R) 36.12

9.8 none 398.5 [M + H]⁺ 0.66 (R) 36.13

31.1 none 438.6 [M + H]⁺ 0.91 (R) 36.14

13.6 none 384.5 [M + H]⁺ 0.51 (R) 36.15

31.0 none 397.5 [M + H]⁺ 1.05 (R) 36.16

8.9 none 426.6 [M + H]⁺ 0.85 (R) 36.17

33.8 none 426.6 [M + H]⁺ 1.01 (R) 36.18

30.0 none 424.6 [M + H]⁺ 0.82 (R) 36.19

19.1 none 398.5 [M + H]⁺ 0.55 (R) 36.20

24.8 none 411.6 [M + H]⁺ 1.14 (R) 36.21

19.6 none 399.5 [M + H]⁺ 0.77 (R) 36.22

26.7 none 480.6 [M + H]⁺ 0.9  (R) 36.23

20.5 none 405.5 [M + H]⁺ 0.82 (R) 36.24

25.6 none 410.5 [M + H]⁺ 0.79 (R) 36.25

25.4 none 454.6 [M + H]⁺ 0.95 (R) 36.26

17.1 none 427.6 [M + H]⁺ 0.8  (R) 36.27

25.8 none 423.5 [M + H]⁺ 0.85 (R) 36.28

10.6 none 426.5 [M + H]⁺ 0.57 (R) 36.29

28.2 none 387.5 [M + H]⁺ 0.75 (R) 36.30

27.4 none 391.4 [M + H]⁺ 0.75 (R) 36.31

4.5 none 440.6 [M + H]⁺ 0.63 (R) 36.32

9.1 none 430.5 [M + H]⁺ 0.7  (R) 36.33

11.9 none 444.6 [M + H]⁺ 0.74 (R) 36.34

22.6 none 395.5 [M + H]⁺ 0.95 (R) 36.35

1.8 none 385.5 [M + H]⁺ 0.6  (R) 36.36

11.8 none 440.6 [M + H]⁺ 0.98 (R) 36.37

10.8 none 381.5 [M + H]⁺ 0.85 (R) 36.38

7.0 none 385.5 [M + H]⁺ 0.66 (R) 36.39

15.6 none 411.6 [M + H]⁺ 1.08 (R) 36.40

21.2 none 396.5 [M + H]⁺ 0.65 (R) 36.41

10.9 none 385.5 [M + H]⁺ 0.66 (R) 36.42

19.0 none 369.5 [M + H]⁺ 0.82 (R) 36.43

7.5 none 438.5 [M + H]⁺ 0.67 (R) 36.44

3.4 none 380.5 [M + H]⁺ 0.62 (R) 36.45

21.3 none 451.5 [M + H]⁺ 1   (R) 36.46

20.7 none 397.5 [M + H]⁺ 1.02 (R) 36.47

21.0 none 411.4 [M + H]⁺ 0.83 (R) 36.48

1.8 none 384.5 [M + H]⁺ 0.62 (R) 36.49

26.1 none 426.6 [M + H]⁺ 0.85 (R) 36.50

15.8 none 412.6 [M + H]⁺ 0.74 (R) 36.51

4.4 none 384.5 [M + H]⁺ 0.63 (R) 36.52

4.6 none 412.5 [M + H]⁺ 0.57 (R) 36.53

2.1 none 386.5 [M + H]⁺ 0.71 (R) 36.54

25.0 none 452.6 [M + H]⁺ 1.02 (R) 36.55

7.8 none 400.5 [M + H]⁺ 0.77 (R) 36.56

5.9 none 371.5 [M + H]⁺ 0.89 (R) 36.57

36.8 none 370.5 [M + H]⁺ 0.54 (R) 36.58

27.1 none 466.6 [M + H]⁺ 0.83 (R) 36.59

18.5 none 384.5 [M + H]⁺ 0.61 (R)

Example 37

The compounds described in Table 20 were synthesized according to General Route 31b.

TABLE 20 Yield of final Salt Mass spec HPLC retention Example Structure step (%) type result time (method) 37.1

64.3 TF 384.5 [M + H]+ 0.66 (R) 37.2

58.6 TF 398.5 [M + H]+ 0.7 (R) 37.3

46.9 TF 398.5 [M + H]+ 0.74 (R) 37.4

78.2 TF 398.5 [M + H]+ 0.69 (R) 37.5

94.9 TF 424.6 [M + H]+ 0.85 (R) 37.6

66.2 TF 370.5 [M + H]+ 0.56 (R) 37.7

83.4 TF 426.6 [M + H]+ 0.78 (R) 37.8

79.9 TF 450.5 [M + H]+ 0.98 (R) 37.9

70.7 TF 396.5 [M + H]+ 0.68 (R) 37.10

62.3 TF 384.5 [M + H]+ 0.62 (R) 37.11

72.5 TF 424.6 [M + H]+ 0.88 (R) 37.12

74.5 TF 370.5 [M + H]+ 0.44 (R) 37.13

90.4 TF 384.5 [M + H]+ 0.59 (R) 37.14

20.9 NONE 384.5 [M + H]+ 0.7 (R) 37.15

49.5 TF 412.6 [M + H]+ 0.98 (R) 37.16

55.4 TF 356.5 [M + H]+ 0.49 (R) 37.17

53.5 TF 410.5 [M + H]+ 0.79 (R) 37.18

72.4 TF 384.5 [M + H]+ 0.6 (R) 37.19

97.5 TF 440.6 [M + H]+ 0.62 (R) 37.20

70.0 TF 358.5 [M + H]+ 0.63 (R) 37.21

22.8 TF 412.5 [M + H]+ 0.83 (R) 37.22

42.6 TF 426.6 [M + H]+ 0.91 (R) 37.23

83.1 TF 464.6 [M + H]+ 0.98 (R) 37.25

45.7 TF 412.6 [M + H]+ 0.9 (R) 37.26

40.6 370.5 [M + H]+ 0.56 (R) 37.27

60.6 TF 398.5 [M + H]+ 0.5 (R) 37.28

93.5 TF 368.5 [M + H]+ 0.49 (R) 37.29

59.0 TF 412.5 [M + H]+ 0.52 (R) 37.30

55.6 TF 426.5 [M + H]+ 0.59 (R) 37.31

48.8 TF 440.6 [M + H]+ 0.63 (R) 37.32

49.1 TF 396.5 [M + H]+ 0.75 (R) 37.33

33.1 TF 370.5 [M + H]+ 0.58 (R) 37.34

67.8 TF 432.5 [M + H]+ 0.96 (R) 37.35

60.0 TF 370.5 [M + H]+ 0.58 (R) 37.36

70.4 TF 398.5 [M + H]+ 0.52 (R) 37.37

73.3 TF 446.6 [M + H]+ 1.14 (R) 37.38

54.4 TF 438.6 [M + H]+ 1 (R) 37.39

25.4 NONE 394.5 [M + H]+ 0.65 (R) 37.40

69.2 TF 450.5 [M + H]+ 1.01 (R) 37.41

64.1 TF 386.5 [M + H]+ 0.78 (R) 37.42

91.0 TF 370.5 [M + H]+ 0.55 (R) 37.43

73.3 TF 446.6 [M + H]+ 0.98 (R) 37.44

83.1 TF 356.5 [M + H]+ 0.48 (R) 37.45

49.3 TF 434.5 [M + H]+ 0.58 (R) 37.46

50.0 NONE 460.6 [M + H]+ 1.1 (R) 37.47

26.8 TF 405.5 [M + H]+ 0.77 (R) 37.48

25.6 TF 339.4 [M + H]+ 0.57 (R) 37.49

32.8 TF 371.5 [M + H]+ 0.57 (R) 37.50

35.2 TF 355.5 [M + H]+ 0.77 (R) 37.51

37.3 TF 426.5 [M + H]+ 0.72 (R) 37.52

27.2 TF 353.4 [M + H]+ 0.72 (R) 37.53

36.4 TF 397.5 [M + H]+ 1.03 (R) 37.54

16.6 TF 357.5 [M + H]+ 0.84 (R) 37.55

37.3 TF 385.5 [M + H]+ 0.57 (R) 37.56

16.9 TF 424.5 [M + H]+ 0.61 (R) 37.57

41.0 TF 440.6 [M + H]+ 0.73 (R) 37.58

31.8 TF 437.5 [M + H]+ 0.91 (R) 37.59

42.5 TF 437.5 [M + H]+ 0.95 (R) 37.60

43.2 TF 437.5 [M + H]+ 0.94 (R) 37.61

43.3 TF 371.5 [M + H]+ 0.53 (R) 37.62

33.4 TF 383.5 [M + H]+ 0.97 (R) 37.63

24.8 TF 383.4 [M + H]+ 0.67 (R) 37.64

15.3 TF 356.4 [M + H]+ 0.83 (R) 37.65

20.5 TF 398.5 [M + H]+ 0.55 (R) 37.66

36.0 TF 397.4 [M + H]+ 0.75 (R) 37.67

4.0 TF 357.4 [M + H]+ 0.51 (R) 37.68

38.0 TF 397.5 [M + H]+ 1.04 (R) 37.69

18.8 TF 413.5 [M + H]+ 0.90 (R) 37.70

37.1 TF 383.5 [M + H]+ 0.95 (R) 37.71

38.5 TF 369.5 [M + H]+ 0.83 (R) 37.72

15.8 TF 343.4 [M + H]+ 0.73 (R) 37.73

36.4 TF 345.4 [M + H]+ 0.51 (R) 37.74

56.6 TF 358.5 [M + H]+ 0.59 (R) 37.75

25.3 TF 341.4 [M + H]+ 0.64 (R) 37.76

22.5 TF 357.5 [M + H]+ 0.80 (R) 37.77

36.3 TF 357.5 [M + H]+ 0.79 (R) 37.78

5.5 TF 343.4 [M + H]+ 1.05 (R) 37.79

37.9 TF 393.5 [M + H]+ 0.89 (R) 37.80

23.2 TF 369.5 [M + H]+ 0.86 (R) 37.81

51.2 TF 398.5 [M + H]+ 0.81 (R) 37.82

25.9 TF 357.5 [M + H]+ 0.83 (R) 37.83

35.1 TF 371.5 [M + H]+ 0.91 (R) 37.84

36.8 TF 381.5 [M + H]+ 0.87 (R) 37.85

26.0 TF 325.4 [M + H]+ 0.52 (R) 37.86

19.1 TF 357.5 [M + H]+ 0.82 (R) 37.87

44.4 TF 452.6 [M + H]+ 0.78 (R) 37.88

12.4 TF 371.5 [M + H]+ 0.92 (R) 37.89

53.0 TF 398.5 [M + H]+ 0.97 (R) 37.90

57.9 TF 398.5 [M + H]+ 0.81 (R) 37.91

23.2 TF 353.4 [M + H]+ 0.67 (R) 37.92

24.9 TF 341.4 [M + H]+ 0.66 (R) 37.93

22.7 TF 410.5 [M + H]+ 1.00 (R) 37.94

48.1 TF 369.4 [M + H]+ 0.64 (R) 37.95

39.2 TF 315.4 [M + H]+ 0.52 (R) 37.96

35.1 TF 373.5 [M + H]+ 0.66 (R) 37.97

46.9 TF 443.5 [M + H]+ 0.87 (R) 37.98

24.2 TF 412.6 [M + H]+ 1.04 (R) 37.99

47.1 TF 371.5 [M + H]+ 0.90 (R) 37.100

24.3 TF 384.5 [M + H]+ 0.49 (R) 37.101

40.2 TF 466.6 [M + H]+ 0.85 (R) 37.102

39.2 TF 412.5 [M + H]+ 0.53 (R) 37.103

44.1 TF 369.5 [M + H]+ 0.85 (R) 37.104

12.6 TF 411.4 [M + H]+ 0.92 (R) 37.105

23.2 TF 339.4 [M + H]+ 0.61 (R) 37.106

49.7 TF 440.6 [M + H]+ 1.19 (R) 37.107

18.1 TF 333.4 [M + H]+ 0.50 (R) 37.108

40.2 TF 411.6 [M + H]+ 1.13 (R) 37.109

27.4 TF 339.4 [M + H]+ 0.61 (R) 37.110

25.1 TF 369.5 [M + H]+ 0.86 (R) 37.111

43.5 TF 371.5 [M + H]+ 0.87 (R)

Example 38 (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone

38a 3-Ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 1.23 g (6.17 mmol) 3-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 mL dry MeOH was added at room temperature 1.42 g (7.41 mmol) (1-Diazo-2-oxo-propyl)-phosphonic acid diethyl ester and 1.71 g (12.4 mmol) K₂CO₃ and stirring was continued for 2 h. 10 g of silica gel was added to the reaction mixture, stirring continued for 20 min and then filtered. After evaporation of the solvent the residue was purified by column chromatography (silica, cyclohexane/EtOAc 1:1).

Yield: 0.85 g (71% of theory)

C₁₁H₁₇NO₂ (M=195.26)

Predicted (EI): Molecular ion (M)⁺: 195 observed: Molecular ion (M)⁺: 195

R_(f) value: 0.64 (silica, cyclohexane/EtOAc 2:1).

38b 3-Ethynyl-pyrrolidinium trifluoro-acetate

To 0.85 g (4.35 mmol) 3-Ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 mL DCM was added 2 mL (26.0 mmol) TFA and stirring was continued at room temperature for 3 h. The solvents were evaporated and the residue was used for the next step without further purification.

Yield: 0.91 g (100% of theory)

C₆H₉NO (M=95.15)

Predicted (EI): Molecular ion (M)⁺: 95 observed: Molecular ion (M)⁺: 95

38c 10-[3-(3-Ethynyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

To 150 mg (0.29 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 1.0 mL NMP was added 105 mg (0.33 mmol) TBTU and 120 μL (0.70 mmol) DIPEA and stirring was continued at room temperature for 1 h. Then 60.7 mg (0.29 mmol) of 3-Ethynyl-pyrrolidinium trifluoro-acetate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the purified by HPLC.

Yield: 36 mg (27% of theory)

C₂₅H₃₂N₆O₃ (M=464.56)

predicted: Molecular ion (M+H)⁺: 465 observed: Molecular ion (M+H)⁺: 465

HPLC-MS: 2.1 minutes (Method R)

38d (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone

To 36 mg (0.08 mmol) 10-[3-(3-Ethynyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 10 mL DCM was added 0.4 mL TFA and stirring was continued for 3 h at room temperature. After addition of 2 mL of MeOH 2M NaOH added drop wise to neutralize the reaction mixture. The solvents were evaporated and the residue was purified by HPLC.

Yield: 12 mg (44% of theory)

C₂₀H₂₄N₆O (M=364.44)

predicted: Molecular ion (M+H)⁺: 365 observed: Molecular ion (M+H)⁺: 365

HPLC-MS: 1.3 minutes (Method K)

Example 39 (3-Ethynyl-pyrrolidin-1-yl)-[1-(7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

To 50 mg (0.14 mmol) of (3-Ethynyl-pyrrolidin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidin-3-yl]-methanone in 2 mL of THF and 1 mL of puffer solution (pH 5) was added 11.3 μL (0.15 mmol) of formaldehyde (37% in water) and 35 mg (0.17 mmol) of sodium triacetoxyborohydride. Stirring was continued overnight, the reaction mixture diluted with 1 mL of water, filtered and purified by HPLC.

Yield: 39 mg (76% of theory)

C₂₁H₂₆N₆O (M=378.47)

predicted: Molecular ion (M+H)⁺: 379 observed: Molecular ion (M+H)⁺: 379

HPLC-MS: 1.3 minutes (Method K)

Example 40 (4,4-Difluoro-perhydro-azepin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

40a 4,4-Difluoro-perhydro-azepine-1-carboxylic acid tert-butyl ester

Under an argon atmosphere was added to 2.50 g (11.7 mmol) 4-Oxo-perhydro-azepine-1-carboxylic acid tert-butyl ester in 15 mL DCM at 0° C. slowly 8.7 mL (24.0 mmol) Bis-(2-methoxyethyl)-aminosulfurtrifluoride (50% in THF). After addition of 0.14 mL (2.34 mmol) of ethanole the cooling bath was removed and stirring was continued for 4 h at room temperature. The reaction mixture was neutralized by addition of saturated NaHCO₃-solution, the organic layer was separated, dried and evaporated. The residue was purified by column chromatography (silica, cyclohexane/EtOAc 4:1)

Yield: 0.83 g (30% of theory)

C₁₁H₁₉F₂NO₂ (M=235.27)

Predicted (EI): Molecular ion (M)⁺: 235 observed: Molecular ion (M)⁺: 235

HPLC-MS: 1.9 minutes (Method K)

40b 4,4-Difluoro-perhydro-azepinium chloride

To 830 mg (3.53 mmol) of 4,4-Difluoro-perhydro-azepine-1-carboxylic acid tert-butyl ester was added 5 mL of 2 M aq. HCl and stirring was continued overnight at room temperature. The reaction mixture was freeze dried and used for the next step without further purification

Yield: 0.38 g (62% of theory)

C₆H₁₆F₂N*HCl (M=171.62)

Predicted (EI): Molecular ion (M+H)⁺: 136 observed: Molecular ion (M+H)⁺: 136

HPLC-MS: 1.1 minutes (Method K)

40c 10-[3-(4,4-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 4,4-Difluoro-perhydro-azepinium chloride.

Yield: 190 mg (65% of theory)

C₂₅H₃₄F₂N₆O₃ (M=504.57)

Predicted (EI): Molecular ion (M+H)⁺: 505 observed: Molecular ion (M+H)⁺: 505

HPLC-MS: 1.7 minutes (Method K)

39d (4,4-Difluoro-perhydro-azepin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

To 190 mg (0.38 mmol) 10-[3-(4,4-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 5 mL DCM was added 0.38 mL TFA and stirring was continued overnight at room temperature. To neutralize TFA sat. NaHCO₃-solution was added, the organic layer separated and dried over Na₂SO₄. After filtration and evaporation of the solvent was the residue purified by HPLC.

Yield: 118 mg (78% of theory)

C₂₀H₂₆F₂N₆O (M=404.46)

predicted: Molecular ion (M+H)⁺: 405 observed: Molecular ion (M+H)⁺: 405

HPLC-MS: 1.4 minutes (Method K)

Example 41 (3,3-Difluoro-perhydro-azepin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

41a 3,3-Difluoro-perhydro-azepine-1-carboxylic acid tert-butyl ester

Prepared according to example 40a starting from 5.0 g (23.4 mmol) of 3-Oxo-perhydro-azepine-1-carboxylic acid tert-butyl ester.

Yield: 0.66 g (12% of theory)

C₁₁H₁₉F₂NO₂ (M=235.27)

Predicted (EI): Molecular ion (M+H)⁺: 236 observed: Molecular ion (M+H)⁺: 236

HPLC-MS: 1.9 minutes (Method K)

41b 3,3-Difluoro-perhydro-azepinium chloride

Prepared according to example 40b starting from 655 mg (2.78 mmol) of 3,3-Difluoro-perhydro-azepine-1-carboxylic acid tert-butyl ester

Yield: 478 mg (100% of theory)

C₆H₁₆F₂N*HCl (M=171.62)

Predicted (EI): Molecular ion (M+H)⁺: 136 observed: Molecular ion (M+H)⁺: 136

HPLC-MS: 1.1 minutes (Method K)

41c 10-[3-(3,3-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 3,3-Difluoro-perhydro-azepinium chloride.

Yield: 160 mg (55% of theory)

C₂₅H₃₄F₂N₆O₃ (M=504.57)

Predicted (EI): Molecular ion (M+H)⁺: 505 observed: Molecular ion (M+H)⁺: 505

HPLC-MS: 1.7 minutes (Method K)

41d (3,3-Difluoro-perhydro-azepin-1-yl)-[1-(6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

Prepared according to example 40d starting from 160 mg (0.32 mmol) of 10-[3-(3,3-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester.

Yield: 106 mg (83% of theory)

C₂₀H₂₆F₂N₆O (M=404.46)

predicted: Molecular ion (M+H)⁺: 405 observed: Molecular ion (M+H)⁺: 405

HPLC-MS: 1.4 minutes (Method K)

Example 42 (3,3-Dimethyl-pyrrolidin-1-yl)-[1-(5-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

42a 10-(3-Carboxy-azetidin-1-yl)-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

To 2.24 g (6.65 mmol) 5-methyl-10-chloro-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (example 3d) in 100 mL ethanol was added 2.2 mL (13.3 mmol) of diisopropylethylamine followed by 0.74 g (7.32 mmol) 3-azetidine carboxylic acid and the reaction was stirred at 90° C. overnight. Addition of a further 1.7 g (1.66 mmol) of 3-azetidine carboxylic acid and 2.2 mL (13.3 mmol) of diisopropylethylamine followed by heating at 90° C. for an additional 24 hrs was required for complete conversion. Evaporation of the solvent yielded the crude product which was determined to be the diisopropylethylamine salt by NMR analysis.

Yield: 4.39 g (127% of theory, residual diisopropylethylamine present)

C₁₈H₂₆N₆O₄ (M=401.47)

predicted: Molecular ion (M+H)⁺: 402 observed: Molecular ion (M+H)⁺: 402

HPLC-MS: 1.4 minutes (Method B)

42b 10-[3-(3,3-Dimethyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

To 300 mg (0.57 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 6.0 mL DMF was added 484 mg (1.51 mmol) TBTU and 243 μL (1.41 mmol) DIPEA and stirring was continued at room temperature for 30 min. Then 84.3 mg (0.62 mmol) of 3,3-Dimethyl-pyrrolidinium chloride was added and the reaction mixture was stirred additional 4 h. The reaction mixture was filtered and the purified by HPLC.

Yield: 162 mg (59% of theory)

C₂₆H₃₈N₆O₃ (M=482.62)

predicted: Molecular ion (M+H)⁺: 483 observed: Molecular ion (M+H)⁺: 483

HPLC-MS: 3.0 minutes (Method R)

42c (3,3-Dimethyl-pyrrolidin-1-yl)-[1-(5-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidin-3-yl]-methanone

Prepared according to example 38d starting from 162 mg (0.34 mmol) of 10-[3-(3,3-Dimethyl-pyrrolidine-1-carbonyl)-azetidin-1-yl]-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester.

Yield: 65 mg (51% of theory)

C₂₁H₃₀N₆O (M=382.50)

Predicted (ESI): Molecular ion (M+H)⁺: 383 observed: Molecular ion (M+H)⁺: 383

HPLC-MS: 1.0 minutes (Method K)

Example 43 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidine-3-carboxylic acid [1-(3-methyl-but-2-enyl)-piperidin-4-yl]-amide

43a [1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

To 0.75 g (3.75 mmol) Piperidin-4-yl-carbamic acid tert-butyl ester and 0.78 g (5.62 mmol) K2CO3 in 5 mL THF was added drop wise 0.65 mL (5.62 mmol) of 1-Bromo-3-methyl-but-2-ene and stirring was continued for 2 h at room temperature. The reaction mixture was filtered, the filtrate was concentrated and the residue purified by column chromatography (silica, EtOAc).

Yield: 0.59 g (58% of theory)

C₁₅H₂₈N₂O₂ (M=268.40)

predicted: Molecular ion (M+H)⁺: 269 observed: Molecular ion (M+H)⁺: 269

HPLC-MS: 2.0 minutes (Method K)

43b 1-(3-Methyl-but-2-enyl)-piperidin-4-yl-ammonium bis trifluoroacetate

To 0.59 g (2.18 mmol) [1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-carbamic acid tert-butyl ester in 10 mL of DCM was added 2.19 mL TFA and stirring was continued for 2.5 h at room temperature. The reaction mixture was concentrated and the residue used without further purification.

Yield: 0.90 g (100% of theory)

C₁₅H₂₈N₂O₂*2C₂HF₃O₂ (M=396.33)

predicted: Molecular ion (M+H)⁺: 169 observed: Molecular ion (M+H)⁺: 169

HPLC-MS: 2.5 minutes (Method L)

43c 10-{3-[1-(3-Methyl-but-2-enyl)-piperidin-4-ylcarbamoyl]-azetidin-1-yl}-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester

Prepared according to example 38c starting from 150 mg (0.29 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 126 mg (0.32 mmol) of 1-(3-Methyl-but-2-enyl)-piperidin-4-yl-ammonium bis trifluoroacetate.

Yield: 70 mg (45% of theory)

C₂₉H₄₃N₇O₃ (M=537.70)

Predicted: Molecular ion (M+H)⁺: 538 observed: Molecular ion (M+H)⁺: 538

HPLC-MS: 1.2 minutes (Method K)

43d 1-(6,7,8,9-Tetrahydro-5H-1,4,7,10a-tetraaza-cyclohept[f]inden-10-yl)-azetidine-3-carboxylic acid [1-(3-methyl-but-2-enyl)-piperidin-4-yl]-amide

To 70 mg (0.13 mmol) 10-{3-[1-(3-Methyl-but-2-enyl)-piperidin-4-ylcarbamoyl]-azetidin-1-yl}-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 2 mL of DCM was added 0.13 mL TFA and stirring was continued for 2.5 h at room temperature. The reaction mixture was concentrated and the residue, after addition of small amounts of 1N NaOH and MeOH, purified by HPLC.

Yield: 48 mg (85% of theory)

C₂₄H₃₅N₇O (M=437.58)

Predicted (EI): Molecular ion (M)⁺: 437 observed: Molecular ion (M)⁺: 437

HPLC-MS: 1.0 minutes (Method K)

Biological Data

EC₅₀ values of representative compounds described in the Examples are compiled in the following Table 21. The values have been obtained as described hereinbefore.

TABLE 21 Biological activity of compounds/5-HT2C EC₅₀ values Ex. No. EC₅₀ (nM) Ex. No. EC₅₀ (nM) Ex. No. EC₅₀ (nM) 1 908 31.88 71 35.20 326 1.1 108 31.89 133 35.21 75 1.2 127 31.90 465 35.22 82 1.3 18 31.91 2006 35.23 105 1.4 2419 31.92 921 35.24 120 1.5 193 31.93 786 35.25 666 1.6 23 31.94 182 35.26 115 1.7 42 31.95 41 35.27 93 1.8 5 31.96 26 35.28 189 1.9 26 31.97 156 35.29 114 1.10 96 31.98 45 35.30 40 1.11 504 31.99 64 35.31 129 1.12 507 31.100 158 35.32 411 1.13 2304 31.101 62 35.33 90 1.14 1335 31.102 36 35.34 65 1.15 10 31.104 215 35.35 67 1.21 1149 31.105 111 35.36 90 1.22 1412 31.106 184 35.37 47 1.23 522 31.107 52 35.41 9 1.24 1313 31.108 113 35.42 212 1.26 160 31.109 83 35.43 207 1.36 1849 31.110 30 35.44 256 1.37 1301 31.111 56 35.45 129 1.38 1811 31.112 131 35.46 495 1.39 2575 31.113 27 35.47 66 1.40 1290 31.114 38 35.48 526 1.42 9600 31.115 55 35.49 137 1.46 582 31.116 60 35.50 208 1.50 924 31.117 291 35.51 126 1.54 1641 31.118 11 35.52 147 1.55 2779 31.119 82 35.53 324 1.57 2955 31.120 103 35.54 85 1.58 4707 31.121 22 35.55 115 1.60 1587 31.122 33 36.1 69 1.61 4713 31.123 9 36.2 563 1.62 2073 31.124 94 36.3 108 1.63 2680 31.125 38 36.4 252 1.65 4898 31.126 47 36.5 51 1.66 1661 31.127 1285 36.6 67 2 4 31.128 54 36.7 106 2.1 7 31.130 57 36.8 38 2.2 56 31.131 74 36.9 379 3 1815 31.132 254 36.10 374 3.1 3 31.133 60 36.11 138 4 679 31.134 117 36.12 73 5 570 31.135 46 36.13 114 6 156 31.136 78 36.14 364 6.1 365 31.137 71 36.15 154 7 2575 31.138 71 36.16 282 7.1 764 31.139 16 36.17 88 7.2 4564 31.140 65 36.18 77 7.3 484 31.141 87 36.19 257 7.4 5 31.142 186 36.20 63 7.5 592 31.143 49 36.21 161 8 272 31.144 66 36.22 181 8.1 75 31.145 94 36.23 124 8.2 105 31.146 91 36.24 228 9 71 31.147 78 36.25 202 9.1 818 31.148 19 36.26 191 10 846 31.149 45 36.27 89 11 161 31.150 240 36.28 380 12 253 31.151 319 36.29 279 13 628 31.152 77 36.30 117 14 678 31.153 86 36.31 187 15 43 31.154 40 36.32 288 15.1 6 31.155 52 36.33 195 15.2 3 31.156 135 36.34 885 15.3 10 31.157 34 36.35 114 15.4 25 31.158 1229 36.36 256 15.5 7 31.159 32 36.37 61 15.6 5 31.160 458 36.38 86 15.7 12 31.161 15 36.39 911 15.8 6 31.162 187 36.40 283 15.9 7 31.163 108 36.41 337 15.10 20 31.164 111 36.42 741 15.11 20 31.165 72 36.43 264 15.12 9 31.166 97 36.44 214 15.13 28 31.167 101 36.45 87 15.14 2 31.168 107 36.46 143 15.15 2 31.169 33 36.47 130 15.16 3 31.170 64 36.48 269 15.17 31 31.171 967 36.49 78 15.18 140 31.172 765 36.50 81 15.19 21 31.173 440 36.51 81 15.20 26 31.174 116 36.52 181 15.21 29 31.175 64 36.53 87 15.22 141 31.176 95 36.54 97 15.23 47 31.177 623 36.55 87 15.24 54 31.178 109 36.56 217 15.25 212 31.179 1695 36.57 287 15.26 163 31.180 36 36.58 447 15.27 7 31.181 84 36.59 173 15.28 24 31.182 9 36.60 809 16 211 31.183 308 37.1 3 16.1 82 31.184 287 37.2 1 17 15 31.185 1465 37.3 3 18 451 31.186 68 37.4 4 18.1 119 31.187 1010 37.5 2 19 139 31.188 101 37.6 2 20 350 31.189 315 37.7 15 20.1 359 31.190 4 37.8 8 20.2 658 31.191 600 37.9 3 20.3 469 31.192 359 37.10 2 20.4 543 31.193 64 37.11 2 20.5 358 31.194 2556 37.12 27 20.6 38 31.195 7 37.13 1 20.7 424 31.196 195 37.14 1 20.8 939 31.197 122 37.15 3 20.9 84 31.198 1805 37.16 5 20.10 181 31.199 48 37.17 3 20.11 116 31.200 28 37.18 2 20.12 959 31.201 24 37.19 5 20.13 347 31.202 162 37.20 26 20.14 23 31.203 67 37.21 2 20.15 180 31.204 33 37.22 2 21 5200 31.205 116 37.23 6 22 1016 31.206 146 37.25 3 23 114 31.207 43 37.26 2 24 588 31.208 62 37.27 14 25 106 31.209 95 37.28 6 25.1 77 31.211 31 37.29 10 25.2 12 31.212 34 37.30 8 26 10 31.213 103 37.31 7 27 49 31.214 471 37.32 22 27.1 37 31.215 155 37.33 7 27.2 55 31.216 847 37.34 6 29 81 31.217 56 37.35 4 31.1 89 31.218 40 37.36 10 31.2 14 31.219 124 37.37 9 31.3 885 31.220 55 37.38 3 31.4 685 31.221 625 37.39 7 31.5 742 31.222 96 37.40 12 31.6 5938 31.223 39 37.41 8 31.7 3303 31.224 45 37.42 2 31.8 94 31.225 111 37.43 6 31.9 726 31.226 74 37.44 2 31.10 1669 31.227 92 37.45 2 31.11 306 31.228 42 37.46 2 31.12 820 31.229 108 37.47 126 31.13 99 31.230 54 37.48 141 31.14 87 31.231 27 37.49 44 31.15 342 31.232 95 37.50 51 31.16 2393 31.233 106 37.51 11 31.17 276 31.234 380 37.52 61 31.18 458 31.235 84 37.53 20 31.19 50 31.236 31 37.54 118 31.21 727 31.237 11 37.55 66 31.22 85 31.238 13 37.56 10 31.23 346 31.239 80 37.57 27 31.24 53 31.240 29 37.58 224 31.25 1508 31.241 84 37.59 47 31.26 29 31.242 86 37.60 49 31.27 274 31.243 82 37.61 64 31.28 314 31.244 62 37.62 10 31.29 87 31.245 26 37.63 84 31.30 338 31.246 266 37.64 4 31.31 2154 31.247 28 37.65 5 31.32 49 31.248 25 37.66 42 31.33 196 31.249 16 37.67 67 31.34 91 31.250 9 37.68 39 31.35 50 32.1 2403 37.69 73 31.36 57 32.2 8290 37.70 69 31.37 68 32.3 1962 37.71 114 31.38 790 32.4 4265 37.72 91 31.39 44 32.5 6550 37.73 88 31.40 40 32.6 2782 37.74 29 31.41 58 32.7 1527 37.75 137 31.42 37 33.1 19 37.76 65 31.43 35 33.2 20 37.77 95 31.44 113 33.3 12 37.78 82 31.45 575 34 611 37.79 62 31.47 21 34.1 53 37.80 124 31.48 38 34.2 150 37.81 40 31.49 51 34.3 418 37.82 33 31.50 51 34.4 24 37.83 51 31.51 85 34.5 246 37.84 62 31.52 199 34.6 65 37.85 94 31.53 8 34.14 369 37.86 41 31.54 107 34.18 388 37.87 9 31.55 600 34.2 135 37.88 36 31.56 43 34.23 594 37.89 19 31.57 37 34.24 136 37.90 12 31.58 53 34.26 1153 37.91 301 31.59 147 34.27 46 37.92 161 31.60 57 34.28 188 37.93 12 31.61 176 34.29 96 37.94 228 31.62 925 34.34 2091 37.95 742 31.63 31 34.35 472 37.96 111 31.64 199 34.36 353 37.97 8 31.66 360 34.37 2378 37.98 25 31.68 46 34.38 290 37.99 92 31.69 36 34.39 666 37.100 14 31.70 175 35 141 37.101 70 31.71 366 35.1 41 37.102 67 31.72 819 35.2 184 37.103 68 31.73 252 35.3 98 37.104 106 31.74 175 35.4 81 37.105 139 31.76 81 35.5 112 37.106 9 31.78 83 35.6 266 37.107 91 31.79 20 35.7 67 37.108 72 31.80 30 35.11 926 37.109 79 31.81 33 35.13 1361 37.110 255 31.82 154 35.14 477 37.111 139 31.83 8 35.15 20 38 6 31.84 126 35.16 92 39 78 31.85 23 35.17 88 40 6 31.86 79 35.18 636 41 7 31.87 36 35.19 87 42 31 31.88 71 43 8

Example A Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains:

active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg     -   Diameter: 10 mm, biplanar, facetted on both sides and notched on         one side.

Example B Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains:

active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg

Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

-   -   Weight of tablet: 300 mg     -   die: 10 mm, flat

Example C Hard Gelatine Capsules Containing 150 mg of Active Substance Composition:

1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules.

-   -   Capsule filling: approx. 320 mg     -   Capsule shell: size 1 hard gelatine capsule.

Example D Suppositories Containing 150 mg of Active Substance Composition:

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg

Preparation:

After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example E Ampoules Containing 10 mg Active Substance Composition:

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilled water ad 2.0 mL

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 mL ampoules.

Example F Ampoules Containing 50 mg of Active Substance Composition:

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilled water ad 10.0 mL

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 mL ampoules. 

1. A compound of formula (I)

wherein: X denotes a divalent 4- to 10-membered monocylic, 7- to 12-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a carbocycle, a monoaza-heterocycle and a diaza-heterocycle, which is linked to the adjacent groups via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via two nitrogen atoms,  wherein 1 or 2 —CH₂— groups optionally are replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or  1 —CH₂— group optionally is replaced by the divalent group >C═C(R^(x))₂, wherein R^(x) independently denotes H or C₁₋₃-alkyl, and/or  wherein in an unsaturated group 1 double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or  wherein in any of the resulting groups one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl, C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl, thiohydroxy, C₁₋₆-alkylthio, C₃₋₆-alkenylthio, C₃₋₆-alkynylthio, amino, C₁₋₆-alkyl-amino, C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino, di-(C₁₋₆-alkyl)-amino, di-(C₃₋₆-alkenyl)-amino, di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl, C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl, amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl, C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl, hydroxycarbonyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino, C₂₋₆-alkenyl-carbonylamino, C₂₋₆-alkynyl-carbonylamino, C₁₋₆-alkyl-sulphonyl, C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl, C₁₋₆-alkyl-sulphonylamino, C₂₋₆-alkenyl-sulphonylamino, C₂₋₆-alkynyl-sulphonylamino, aminosulphonyl, C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)-aminosulphonyl, C₃₋₆-alkenylaminosulphonyl, di-(C₃₋₆-alkenyl)-aminosulphonyl, C₃₋₆-alkynylaminosulphonyl, or di-(C₃₋₆-alkynyl)-aminosulphonyl groups, while the substituents may be identical or different, and/or  wherein one ring member nitrogen atom optionally is substituted by a C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, hydroxy, hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl, C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl, C₁₋₆-alkyl-sulphonyl, C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl, aminosulphonyl, phenyl or phenyl-C₁₋₃-alkyl group, Y is absent or denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 or 2 —CH₂— groups optionally are replaced independently by O, S, carbonyl, sulfonyl, or —NH—, with the proviso that two heteroatoms are not directly linked together, or  wherein 1 —CH₂— group is replaced by O, S, carbonyl, sulfonyl, or —NH—, and additionally a —CH₂—CH₂— subgroup is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, or —NH—C(O)—, with the proviso that two heteroatoms are not directly linked together, and  wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C₃₋₆-cycloalkyl or phenyl group, or by a straight-chained or branched C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, phenyl-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl, or C₁₋₆-alkyl-sulphonyl group, and/or  wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are replaced by halogen atoms, trifluoromethyl, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, phenyl, phenyl-C₁₋₆-alkyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl-carbonyl, C₁₋₆-alkoxy-carbonyl, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₆-alkyl-sulphonyl groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH₂)_(m)— bridge, wherein m is 2, 3, 4, or 5, W denotes H or an optionally substituted straight-chained or branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or  an optionally substituted cyclo-C₃₋₉-alkyl group, wherein independently in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to adjacent carbon atoms optionally are replaced to form a double bond within the ring, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and the resulting group is bound via a saturated or unsaturated carbon atom, or in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C₂₋₅-alkylenyl bridge or 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the resulting polycyclic groups one or two —CH₂— groups optionally are replaced by —NH— (or N-atoms for replacement of —CH< members), >N—(C₁₋₆-alkyl), O, S, carbonyl, or sulfonyl, and/or two —CH₂— groups in relative 1,3-position within a C₄₋₅-alkylenyl bridge optionally are replaced by O atoms, and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C₄₋₈-alkyl group one, two or three ring members optionally are replaced independently of each other by —NH—, >N—(C₁₋₆-alkyl) (or N-atoms for replacement of —CH< members), O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom,  and wherein any of the resulting open-chained or cyclic groups independently 1 to 4 hydrogen atoms optionally are replaced by C₁₋₆-alkyl or C₁₋₆-alkoxy groups, and/or  any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group,  an optionally substituted cyclo-C₃₋₈-alkyl-aryl or cyclo-C₃₋₈-alkyl-hetaryl group, wherein the cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or N-atoms for replacement of —CH< members), >N(C₁₋₃-alkyl), O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, or if Y is absent W additionally denotes  a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, 5, 6 or 7, attached in relative 1,1-position (geminal) to a carbon atom of group X, including the options: if p is 3, 4, 5, 6 or 7 it follows that 1 —CH₂— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C₁₋₆-alkyl)-, or if p is 4, 5, 6 or 7 it follows that a —CH₂—CH₂— group optionally is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)-, —N(C₁₋₆-alkyl)-C(O)—, or —CH═CH—, wherein the double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group,  a divalent —(CH₂)_(q)— group, wherein q is 3, 4, or 5, attached in relative 1,2-position (vicinal) to carbon atoms of group X, including the options: that 1 —CH₂— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C₁₋₆-alkyl)-, or a —CH₂—CH₂— group optionally is replaced by —C(O)—O—, —O—C(O)—, —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)-, —N(C₁₋₆-alkyl)-C(O)—, or that in the resulting 5-, 6- and 7-membered carbocyclic ring 2, 4 or 6 hydrogen atoms optionally are replaced by 1, 2 or 3 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl, sulfonyl, —NH— or —N(C₁₋₆-alkyl)-, and/or one —CH═ unit is replaced by —N═,  a divalent —(CH₂)_(r)— group, wherein r is 5, 6 or 7, attached in relative 1,3-position to carbon atoms as binding sites of group X, including the options: that in the resulting 8-, 9- or 10-membered carbocyclic ring 2, 4, 6, 8 or 10 hydrogen atoms optionally are replaced by 1, 2, 3, 4 or 5 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, and/or that in the resulting 8-, 9- or 10-membered carbocyclic ring 1 hydrogen atom attached to the carbon atom in position 2 relative to the binding sites of group X and 1 hydrogen atom attached to a carbon atom of the —(CH₂)_(r)— group in position 6 or 7 relative to the binding sites of group X optionally are replaced by a bond (C₀-bridge) to form a bicyclic ring system condensed with the group X, R¹ denotes H, C₁₋₆-alkyl, C₃₋₆-alkenyl or C₃₋₆-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or cyclo-C₃₋₇-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, hydroxy or C₁₋₆-alkoxy, any of those C₁₋₆-alkyl, C₂₋₆-alkenyl or C₃₋₆-alkynyl groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano or cyclo-C₃₋₇-alkyl-group, R⁴ and R⁵ independently denote H, halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₆-alkyl, C₂₋₆-alkenyl or C₃₋₆-alkynyl groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, by a cyano, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₆-alkyl, cyclo-C₃₋₇-alkyl, cyano, hydroxy, C₁₋₆-alkoxy, amino, C₁₋₆-alkyl-amino, or di-(C₁₋₆-alkyl)-amino groups, wherein, if not specified otherwise, any alkyl groups or subgroups mentioned hereinbefore are straight-chained or branched, the term “aryl” as used hereinbefore, either alone or as a sub-moiety within another substituent, if not otherwise specified means either an optionally substituted aromatic monocyclic or multicyclic system, for example a phenyl or a naphthyl group, the term “hetaryl” as used hereinbefore, either alone or as a sub-moiety within another substituent, if not otherwise specified denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic heteroaromatic groups comprising one, two or three heteroatoms selected from oxygen, sulphur and nitrogen, linked through a carbon atom or, if present, through a nitrogen atom, and optionally substituted at carbon atoms and/or a nitrogen atoms, and wherein the expression “substituted” or “optionally substituted” as used hereinbefore if not otherwise specified means substitution with one, two, three, four or more substituents attached to carbon atoms selected from the group consisting of halogen atoms (fluorine, chlorine, bromine or iodine atoms), C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₈-alkyl, cyclo-C₃₋₇-alkenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl, C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl, C₃₋₆-alkenoxy-C₃₋₆-alkenyl, C₃₋₆-alkenoxy-C₃₋₆-alkynyl, C₃₋₆-alkynoxy-C₁₋₆-alkyl, C₃₋₆-alkynoxy-C₃₋₆-alkenyl, C₃₋₆-alkynoxy-C₃₋₆-alkynyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidino, piperidino, thiohydroxy, C₁₋₆-alkylthio, C₃₋₆-alkenylthio, C₃₋₆-alkynylthio, amino, C₁₋₆-alkyl-amino, C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino, di-(C₁₋₆-alkyl)-amino, di-(C₃₋₆-alkenyl)-amino, di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl, C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl, amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl, C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl, hydroxycarbonyl, phenyl, phenyl-C₁₋₃-alkyl, phenyloxy, phenyl-C₁₋₃-alkoxy, phenyloxy-C₁₋₃-alkyl, phenylcarbonyl, pyridyl, thiazolyl; pyridyl-carbonyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₂₋₆-alkenyl-carbonylamino, C₂₋₆-alkynyl-carbonylamino, formyl-C₁₋₆-alkyl-amino, formyl-C₃₋₆-alkenyl-amino, formyl-C₃₋₆-alkynyl-amino, C₁₋₆-alkyl-carbonyl-C₁₋₆-alkyl-amino, C₂₋₆-alkenyl-carbonyl-C₁₋₆-alkyl-amino, C₂₋₆-alkynyl-carbonyl-C₁₋₆-alkyl-amino, C₁₋₆-alkyl-carbonyl-C₃₋₆-alkenyl-amino, C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkenyl-amino, C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkenyl-amino, C₁₋₆-alkyl-carbonyl-C₃₋₆-alkynyl-amino, C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkynyl-amino, C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkynyl-amino, C₁₋₆-alkyl-sulphonyl, C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl, C₁₋₆-alkyl-sulphonylamino, C₂₋₆-alkenyl-sulphonylamino, C₂₋₆-alkynyl-sulphonylamino, C₁₋₆-alkyl-sulphonyl-C₁₋₆-alkylamino, C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkenylamino, C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkynylamino, C₂₋₆-alkenyl-sulphonyl-C₁₋₆-alkylamino, C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkenylamino, C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkynylamino, C₂₋₆-alkynyl-sulphonyl-C₁₋₆-alkylamino, C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkenylamino, C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkynylamino, aminosulphonyl, C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)-aminosulphonyl, C₃₋₆-alkenylaminosulphonyl, di-(C₃₋₆-alkenyl)-aminosulphonyl, C₃₋₆-alkynylaminosulphonyl and di-(C₃₋₆-alkynyl)-aminosulphonyl groups, while the substituents may be identical or different and wherein any alkyl groups or alkyl sub-moieties optionally are partially or fully fluorinated, and wherein any phenyl, pyridyl and thiazolyl groups or phenyl-, pyridyl and thiazolyl-submoieties optionally are substituted with 1 or 2 substituents independently of each other selected from fluorine, chlorine, bromine, iodine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, di-(C₁₋₃-alkyl)-amino C₁₋₃-alkylcarbonyl-amino, C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl-amino, cyano or hydroxy, or with substituents attached to a nitrogen atom selected from the group consisting of C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, cyclo-C₃₋₇-alkyl-C₁₋₆-alkyl, pyrrolidino, piperidino, morpholino, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl, C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl, C₃₋₆-alkenoxy-C₃₋₆-alkenyl, C₃₋₆-alkenoxy-C₃₋₆-alkynyl, C₃₋₆-alkynoxy-C₁₋₆-alkyl, C₃₋₆-alkynoxy-C₃₋₆-alkenyl, C₃₋₆-alkynoxy-C₃₋₆-alkynyl, amino-C₁₋₆-alkyl, C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl, amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl, C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl, hydroxycarbonyl, phenyl, phenyl-C₁₋₆-alkyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, C₁₋₆-alkyl-carbonyl, C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, C₁₋₆-alkyl-sulphonyl, C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl, C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl, aminosulphonyl, C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)-aminosulphonyl, C₃₋₆-alkenylaminosulphonyl, di-(C₃₋₆-alkenyl)-aminosulphonyl, C₃₋₆-alkynylaminosulphonyl and di-(C₃₋₆-alkynyl)-aminosulphonyl groups, while the substituents may be identical or different and wherein any alkyl groups or alkyl sub-moieties optionally are partially or fully fluorinated, and wherein any of the di-(C₁₋₃-alkyl)-amino or di-(C₁₋₆-alkyl)-amino moieties may form optionally with the nitrogen atom a 4 to 8 membered ring system, and wherein any phenyl and pyridyl groups or phenyl- and pyridyl-submoieties optionally are substituted with 1 or 2 substituents independently of each other selected from fluorine, chlorine, bromine, iodine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, C₁₋₃-alkylcarbonyl-amino, cyano or hydroxy, or a salt thereof. 2-8. (canceled)
 9. The compound according to claim 1, wherein X denotes a divalent 4- to 8-membered monocylic, 7- to 10-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a carbocycle, a monoaza-heterocycle and a diaza-heterocycle, which is linked to the adjacent groups via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via both nitrogen atoms, wherein 1 to 2 —CH₂— groups optionally are replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or wherein 1 double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or, wherein one ring member nitrogen atom optionally is substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or C₁₋₃-alkyl-sulphonyl group; Y and W are defined as in claim 1, R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or cyclo-C₃₋₆-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₃-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine atoms, R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₃-alkynyl, cyclo-C₃₋₆-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl, C₂₋₄-alkenyl or C₂₋₃-alkynyl groups being optionally substituted by 1 to 3 fluorine atoms, by a methyl, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, cyano, hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, and di-(C₁₋₃-alkyl)-amino groups, or a salt thereof.
 10. The compound according to claim 1, wherein X denotes a divalent 4- to 8-membered monocylic, 7- to 10-membered spirocyclic or 6- to 12-membered bicyclic saturated, partially or fully unsaturated group selected from a carbocycle, a monoaza-heterocycle and a diaza-heterocycle, which is linked to the adjacent groups via carbon atoms or, if present, via nitrogen atoms, e.g. via one carbon and one nitrogen atom or via both nitrogen atoms, wherein 1 to 2 —CH₂— groups optionally are replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or wherein 1 double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or, wherein one ring member nitrogen atom optionally is substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or C₁₋₃-alkyl-sulphonyl group; Y is absent or denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 —CH₂— group optionally is replaced by O, carbonyl or —NH—, or wherein 1 —CH₂— group is replaced by O or —NH—, and additionally a second —CH₂— group is replaced by carbonyl, or wherein 1 —CH₂— group is replaced by O and additionally a —CH₂—CH₂— subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C₃₋₆-cycloalkyl or phenyl group, or by a straight-chained or branched C₁₋₄-alkyl, phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, or C₁₋₄-alkyl-sulphonyl group, and/or wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are replaced by halogen atoms, trifluoromethyl, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₃₋₆-cycloalkyl, phenyl, phenyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxy-carbonyl, C₁₋₄-alkyl-carbonylamino, C₁₋₄-alkyl-carbonyl-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-aminocarbonyl, or di-(C₁₋₃-alkyl)-aminocarbonyl groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH₂)_(m)— bridge, wherein m is 2, 3, 4, or 5; W is defined as in claim 1, and R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or cyclo-C₃₋₆-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₃-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine atoms, R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₃-alkynyl, cyclo-C₃₋₆-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl, C₂₋₄-alkenyl or C₂₋₃-alkynyl groups being optionally substituted by 1 to 3 fluorine atoms, by a methyl, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, cyano, hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, and di-(C₁₋₃-alkyl)-amino groups, or a salt thereof.
 11. The compound according to claim 1, wherein X denotes a divalent phenyl group or a group selected from formulas (II) to (XIII),

wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, and/or wherein a double bond, if present, optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, and/or wherein in all groups falling under the above definition of X one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or, wherein one ring member nitrogen atom, if present, optionally is substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or C₁₋₃-alkyl-sulphonyl group; Y is absent; W denotes H or an optionally substituted straight-chained or branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or an optionally substituted cyclo-C₃₋₉-alkyl group, wherein independently in a cyclo-C₄₋₇-alkyl group 2 hydrogen atoms attached to adjacent carbon atoms optionally are replaced to form a double bond within the ring, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and the resulting group is bound via a saturated or unsaturated carbon atom, or in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C₂₋₅-alkylenyl bridge, or 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the resulting polycyclic groups one or two —CH₂— groups optionally are replaced by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for replacement of —CH< members), O, or carbonyl, and/or two —CH₂— groups in relative 1,3-position of a C₄₋₅-alkylenyl bridge optionally are replaced by O atoms, and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C₄₋₈-alkyl group one, two or three ring members optionally are replaced independently of each other by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for replacement of —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom, and wherein any of the resulting open-chained or cyclic groups independently 1 to 3 hydrogen atoms optionally are replaced by C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group, an optionally substituted cyclo-C₃₋₈-alkyl-aryl or cyclo-C₃₋₈-alkyl-hetaryl group, wherein the cyclo-C₅₋₈-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or N-atoms for replacement of —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, or a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, or 5, attached in relative 1,1-position (geminal) to a carbon atom of group X, including the options: if p is 3, 4, or 5 it follows that 1 —CH₂— group optionally is replaced by O, carbonyl, —NH— or —N(C₁₋₆-alkyl)-, or if p is 4 or 5 it follows that a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)-, —N(C₁₋₆-alkyl)-C(O)—, or —CH═CH—, wherein the double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, a divalent —(CH₂)_(q)— group, wherein q is 3, or 4 attached in relative 1,2-position (vicinal) to carbon atoms of group X, including the options: that 1 —CH₂— group optionally is replaced by O, carbonyl, —NH— or —N(C₁₋₆-alkyl)-, or a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)-, —N(C₁₋₆-alkyl)-C(O)—, or that in the resulting 5- or 6-membered carbocyclic ring 2, 4 or, in case of the 6-membered ring, also 6 hydrogen atoms optionally are replaced by 1, 2 or 3 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, wherein 1 —CH₂— group optionally is replaced by O, S, carbonyl, —NH— or —N(C₁₋₆-alkyl)-, and/or one —CH═ unit is replaced by —N═, a divalent —(CH₂)₇— group, attached in relative 1,3-position to carbon atoms as binding sites of group X, including the options: that in the resulting 10-membered carbocyclic ring 2, 4, 6, 8 or 10 hydrogen atoms optionally are replaced by 1, 2, 3, 4 or 5 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, and/or that in the resulting 10-membered carbocyclic ring 1 hydrogen atom attached to the carbon atom in position 2 relative to the binding sites of group X and 1 hydrogen atom attached to a carbon atom of the —(CH₂)_(r)— group in position 7 relative to the binding sites of group X optionally are replaced by a bond (C₀-bridge) to form a bicyclic ring system condensed with the group X, e.g. X and W together denote the group

wherein any aryl groups or subgroups mentioned above in the definition of W are selected from optionally substituted phenyl, naphthyl, and tetrahydronaphthyl groups, and wherein any hetaryl groups or subgroups mentioned above in the definition of W are selected from optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, indolyl, indolinyl, benzimidazolyl, tetrahydrobenzimidazolyl, tetrahydrocyclopentaimidazolyl, indazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, hexahydrocycloheptapyrazolyl, benztriazolyl, quinolyl, tetrandyroquinolinly, isoquinolyl, tetrandyroisoquinolinly, cinnolyl, quinoxazolyl and benzpyrimidinyl groups, wherein the expression “substituted” or “optionally substituted” as used herein has the same meaning as in claim 1; and R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or cyclo-C₃₋₆-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₃-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine atoms, R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₃-alkynyl, cyclo-C₃₋₆-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl, C₂₋₄-alkenyl or C₂₋₃-alkynyl groups being optionally substituted by 1 to 3 fluorine atoms, by a methyl, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, cyano, hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, and di-(C₁₋₃-alkyl)-amino groups, or a salt thereof.
 12. The compound according to claim 1, wherein X denotes a group selected from formulas (II), (III), (VI) or (XIII),

wherein 1 —CH₂— group optionally is replaced independently of each other by O or carbonyl, wherein one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be identical or different; Y denotes a —(CH₂)_(n)— group, wherein n is 1, 2, 3, 4, 5 or 6 and wherein 1 —CH₂— group optionally is replaced by O, carbonyl or —NH—, or wherein 1 —CH₂— group is replaced by O or —NH—, and additionally a second —CH₂— group is replaced by carbonyl, or wherein 1 —CH₂— group is replaced by O and additionally a —CH₂—CH₂— subgroup is replaced by —C(O)—NH—, or —NH—C(O)—, and wherein any hydrogen atom of the —NH— groups mentioned hereinbefore optionally and independently is replaced by a C₃₋₆-cycloalkyl or phenyl group, or by a straight-chained or branched C₁₋₄-alkyl, phenyl-C₁₋₃-alkyl, or C₁₋₃-alkyl-carbonyl, and/or wherein 1 or 2 hydrogen atoms attached to carbon atoms optionally are independently replaced by F, Cl, C₁₋₄-alkyl or trifluoromethyl, or 1 hydrogen atom attached to a carbon atom optionally is replaced by C₃₋₆-cycloalkyl, phenyl, phenyl-C₁₋₃-alkyl, hydroxy, or C₁₋₃-alkoxy groups, while the substituents may be identical or different, or 2 geminal hydrogen atoms are replaced by a —(CH₂)_(m)— bridge, wherein m is 2, 3, or 4; W denotes H or an optionally substituted straight-chained or branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or an optionally substituted cyclo-C₃₋₉-alkyl group, wherein independently in a cyclo-C₄₋₇-alkyl group 2 hydrogen atoms attached to adjacent carbon atoms optionally are replaced to form a double bond within the ring, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and the resulting group is bound via a saturated or unsaturated carbon atom, or in a cyclo-C₄₋₉-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C₂₋₅-alkylenyl bridge, or 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3- or 1,4-position optionally are replaced by a C₁₋₅-alkylenyl bridge, wherein any of the resulting polycyclic groups one or two —CH₂— groups optionally are replaced by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for replacement of —CH< members), O, or carbonyl, and/or two —CH₂— groups in relative 1,3-position of a C₄₋₅-alkylenyl bridge optionally are replaced by O atoms, and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C₄₋₈-alkyl group, two or three ring members optionally are replaced independently of each other by —NH—, >N—(C₁₋₆-alkyl), (or N-atoms for replacement of a —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom, and wherein any of the resulting open-chained or cyclic groups independently 1 to 3 hydrogen atoms optionally are replaced by C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group, an optionally substituted cyclo-C₃₋₆-alkyl-aryl or cyclo-C₃₋₆-alkyl-hetaryl group, wherein the cyclo-C₅₋₆-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or a N-atom for replacement of a —CH< member), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine, chlorine or bromine atoms, or by a cyano, hydroxy, C₁₋₃-alkoxy or cyclo-C₃₋₆-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₃-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine atoms, R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₃-alkynyl, cyclo-C₃₋₆-alkyl, hydroxy or C₁₋₃-alkoxy, any of those C₁₋₃-alkyl, C₂₋₄-alkenyl or C₂₋₃-alkynyl groups being optionally substituted by 1 to 3 fluorine atoms, by a methyl, hydroxy, C₁₋₃-alkoxy, or cyclo-C₃₋₅-alkyl-group, or by a phenyl or pyridyl group both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, cyano, hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, and di-(C₁₋₃-alkyl)-amino groups, or a salt thereof.
 13. The compound according to claim 1, wherein X denotes a group selected from formulas (II), (III), (VI), (VII) or (XIII),

wherein 1 —CH₂— group optionally is replaced independently of each other by O, S, carbonyl, or sulfonyl, with the proviso that two heteroatoms are not directly linked together, wherein one or two carbon atoms optionally and independently are substituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-amino-carbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, while the substituents may be identical or different, and/or one ring member nitrogen atom is substituted by C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, cyclo-C₃₋₇-alkyl or cyclo-C₃₋₇-alkenyl; Y denotes a carbonyl group; W denotes H or an optionally substituted straight-chained or branched C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, wherein 1 or 2 methyl groups optionally are replaced by optionally substituted phenyl groups or an optionally substituted cyclo-C₃₋₈-alkyl group, wherein independently in a cyclo-C₄₋₈-alkyl group one or two ring members optionally are replaced independently of each other by —NH—, >N—(C₁₋₆-alkyl) (or N-atoms for replacement of —CH< members), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, and additionally but optionally 2 or 4 hydrogen atoms attached to adjacent ring carbon atoms are replaced to form a double bond or two conjugated double bonds within the ring, either of the double bonds optionally being condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, and/or in a cyclo-C₄₋₅-alkyl group 2 hydrogen atoms attached to the same carbon atom (relative 1,1-position) optionally are replaced by a C₂₋₅-alkylenyl bridge, wherein one —CH₂— group optionally is replaced by —NH—, >N—(C₁₋₆-alkyl), O, or carbonyl or wherein two —CH₂— groups in relative 1,3-position of a C₄₋₅-alkylenyl bridge optionally are replaced O atoms, or wherein a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)- or —N(C₁₋₆-alkyl)-C(O)— and/or 2 hydrogen atoms attached to adjacent carbon atoms within a C₄₋₅-alkylenyl bridge optionally are replaced to form a double bond, which optionally is condensed with an optionally substituted aryl or an optionally substituted 5- or 6-membered hetaryl group, or an optionally substituted cyclo-C₅₋₉-alkyl group, wherein independently 2 hydrogen atoms attached to carbon atoms in relative 1,2-, 1,3-, 1, 4 or 1,5-position optionally are replaced by a C₁₋₃-alkylenyl bridge, wherein any of the resulting polycyclic groups one —CH₂— group optionally is replaced by —NH—, >N—(C₁₋₆-alkyl), O, or carbonyl, wherein any of the resulting groups is bound via a saturated or unsaturated carbon atom or a nitrogen atom, and wherein any of the resulting open-chained or cyclic groups independently 1 to 3 hydrogen atoms optionally are replaced by C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and/or any 1 to 6 hydrogen atoms attached to carbon atoms optionally are replaced by fluorine atoms, or W denotes an optionally substituted aryl or hetaryl group, an optionally substituted cyclo-C₃₋₆-alkyl-aryl or cyclo-C₃₋₆-alkyl-hetaryl group, wherein the cyclo-C₅₋₆-alkyl-submoieties one or two ring members optionally are replaced independently of each other by —NH— (or a N-atom for replacement of a —CH< member), O, or carbonyl, with the proviso that two heteroatoms are not directly linked together, or if Y is absent W additionally denotes a divalent —(CH₂)_(p)— group, wherein p is 2, 3, 4, or 5, attached in relative 1,1-position (geminal) to a carbon atom of group X, including the options: if p is 4 or 5 it follows that 1 —CH₂— group optionally is replaced by O, —NH— or —N(C₁₋₄-alkyl)-, or that a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₄-alkyl)-, —N(C₁₋₄-alkyl)-C(O)—, or —CH═CH—, wherein the double bond optionally is condensed with an aryl or a 5- or 6-membered hetaryl group, a divalent —(CH₂)_(q)— group, wherein q is 3 or 4 attached in relative 1,2-position (vicinal) to carbon atoms of group X, including the options: a —CH₂—CH₂— group optionally is replaced by —C(O)—NH—, —NH—C(O)—, —C(O)—N(C₁₋₆-alkyl)-, —N(C₁₋₆-alkyl)-C(O)—, or that in the resulting 5- or 6-membered carbocyclic ring 2, 4 or, in case of the 6-membered ring, also 6 hydrogen atoms optionally are replaced by 1, 2 or 3 bonds to form a partially or fully unsaturated ring with isolated or conjugated double bonds, wherein 1 —CH₂— group optionally is replaced by O, —NH— or —N(C₁₋₆-alkyl)-, and/or one —CH═ unit is replaced by —N═, the trivalent group

attached in relative 1,2,3-position to carbon atoms * as binding sites of group X, wherein any aryl groups or aryl-subgroups mentioned above in the definition of W are selected from optionally substituted phenyl, naphthyl, and tetrahydronaphthyl groups, and wherein any hetaryl groups or hetaryl-subgroups mentioned above in the definition of W are selected from optionally substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, indolyl, indolinyl, benzimidazolyl, tetrahydrobenzimidazolyl, tetrahydrocyclopentaimidazolyl, indazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, hexahydrocycloheptapyrazolyl, benztriazolyl, quinolyl, tetrandyroquinolinly, isoquinolyl, tetrandyroisoquinolinly, cinnolyl, quinoxazolyl and benzpyrimidinyl groups, wherein the expression “optionally substituted” means that 1, 2 or 3 hydrogen atoms of the respective group independently are optionally replaced by substituents selected from fluorine, chlorine and bromine atoms, atoms, by C₁₋₆-alkyl, trifluoromethyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, cyano, hydroxy, hydroxy-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₁₋₆-alkyl-carbonyl, formyl, amino, C₁₋₄-alkyl-amino, (C₁₋₄-alkyl)₂-amino, phenylamino, N-phenyl-N—(C₁₋₄-alkyl)-amino, pyrrolidino, piperidino, aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-amino-carbonyl, C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl, di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino, C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkyl-carbonyl-(C₁₋₃-alkyl)-amino C₂₋₆-alkenyl-carbonylamino or C₂₋₆-alkynyl-carbonylamino groups, or the expression “optionally substituted” means that 4 hydrogen atoms of the respective group independently are optionally replaced by substituents selected from fluorine atoms and C₁₋₆-alkyl groups, and/or wherein a hydrogen atom attached to a nitrogen atom, if present in the respective group, optionally is replaced by a C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl, cyclo-C₃₋₇-alkyl-C₁₋₃-alkyl, cyclo-C₃₋₇-alkyl-carbonyl, pyrrolidino, piperidino, morpholino, C₁₋₃-alkoxy, C₁₋₃-alkoxy-C₁₋₃-alkyl, phenyl, phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₃-alkoxy-carbonyl or C₁₋₃-alkyl-sulphonyl group and wherein any phenyl and pyridyl groups or phenyl- and pyridyl-submoieties optionally are substituted with 1 or 2 substituents independently of each other selected from fluorine, chlorine, bromine, C₁₋₃-alkyl, C₁₋₃-alkoxy, amino, C₁₋₃-alkyl-amino, C₁₋₃-alkylcarbonyl-amino or hydroxy; R¹ denotes H, C₁₋₄-alkyl, C₃₋₄-alkenyl or C₃₋₄-alkynyl, any of those groups being optionally substituted by 1 to 3 fluorine or chlorine atoms, or by a or cyclo-C₃₋₆-alkyl-group, R² and R³ independently denote H, halogen, C₁₋₃-alkyl, any of those C₁₋₃-alkyl groups being optionally substituted by 1 to 3 fluorine atoms, R⁴ and R⁵ independently denote H, halogen, C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl, any of those C₁₋₃-alkyl, groups being optionally substituted by 1 to 3 fluorine atoms, by a methyl, or cyclo-C₃₋₅-alkyl group, or by a phenyl or pyridyl group, both optionally substituted independently by 1, 2 or 3 substituents selected from halogen atoms, C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, amino, and C₁₋₃-alkyl-amino groups. or a salt thereof.
 14. A physiologically acceptable salt of a compound according to claim 1 with inorganic or organic acids or bases.
 15. A pharmaceutical composition containing a compound according to claim 1, or a physiologically acceptable salt with inorganic or organic acids or bases, optionally together with one or more inert carriers and/or diluents.
 16. A method of using a compound according to claim 1, or a physiologically acceptable salt with inorganic or organic acids or bases, for treatment or prevention of diseases or conditions which can be influenced by agonising the activity of the 5-HT2C receptor, such as metabolic and CNS-related disorders. 